Aromatic compounds, methods for their preparation and use

Abstract

Provided are an aromatic compound as shown in Formula A or a pharmaceutically acceptable salt thereof, a preparation method and applications thereof. The aromatic compound has good inhibitory effect on KRAS, especially KRAS G12C.

Description

[0001] This application claims priority to Chinese Patent Application No. 2020113346910, filed on November 24, 2020; and to Chinese Patent Application No. 2021113580344, filed on November 16, 2021. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to an aromatic compound, its preparation method, and its application. Background Technology

[0003] KRAS is a major member of the RAS gene family. Among RAS family members, oncogenic mutations are most common in KRAS (85%), with KRAS G12C being the most common mutation type, while HRAS and NRAS are less common. KRAS gene mutations are present in one-seventh of all metastatic cancers in humans, making it the most common oncogenic gene mutation: the mutation rate exceeds 30% in lung adenocarcinoma, over 40% in colorectal cancer, and over 90% in pancreatic cancer. KRAS gene mutations are considered "the most difficult mutations to treat." After years of effort, KRAS inhibitors have entered phase I clinical trials abroad. This invention focuses on the development of novel KRAS inhibitors and KRAS degrading agents. The aim is to provide cancer patients with a new treatment approach, addressing common drug resistance issues and extending the effective treatment period of drugs. Summary of the Invention

[0004] This invention provides an aromatic compound, its preparation method, and its application. The aromatic compound of this invention exhibits good inhibitory effects on KRAS, especially KRAS G12C.

[0005] This invention provides a compound as shown in Formula A or a pharmaceutically acceptable salt thereof.

[0006]

[0007] in,

[0008] Z is O or NR 5 ;

[0009] R 5 C1-C6 alkyl, R 5-5 Substituted or unsubstituted C2-C6 alkenyl groups

[0010] R 5-1 R 5-2 R 5-3 R 5-4 R 5-6 and R5-7 Independently hydrogen, by R 5-1a Substituted or unsubstituted C1-C6 alkyl groups, R 5 -2a Substituted or unsubstituted C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy groups;

[0011] R 5-5 It is either cyano or halogen;

[0012] R 5-1a For R 5-1a-1 Substituted or unsubstituted C1-C6 alkoxy groups;

[0013] R 5-1a-1 It is a C1-C6 alkoxy group;

[0014] R 5-2a It is a C1-C6 alkyl, cyano, or halogen;

[0015] R 1 It is hydrogen or C1-C6 alkyl;

[0016] R 2 OR 2-1 、Being R 2-2 Substituted or unsubstituted C6-C 15 Aryl or R 2-3 5-15-membered heteroaryl groups, with substituted or unsubstituted heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms being 1, 2, 3, or 4;

[0017] R 2-1 For R 2-1a Substituted or unsubstituted C6-C 15 Aryl;

[0018] R 2-2 R 2-3 and R 2-1a Independently hydroxyl, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy,

[0019] R 2-2a and R 2-2b Independently for R 2-2a-1 Substituted or unsubstituted C1-C6 alkyl groups;

[0020] R 2-2a-1 For R 2-2a-1a Substituted or unsubstituted C1-C6 alkoxy groups;

[0021] R 2-2a-1a It is a C1-C6 alkoxy group;

[0022] R3 R 3-1 substituted or unsubstituted C6-C 15 aryl, or a 5-15 membered heteroaryl group optionally substituted with R 3-2 substituted or unsubstituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4";

[0023] R 3-1 and R 3-2 are independently hydroxyl, cyano, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, -L-R 3-1a ;

[0024] -L- is a terminus is attached to R 3-1a , and a terminus is attached to C6-C 15 aryl or a 5-10 membered heteroaryl group in which "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3";

[0025] n1, n2, n3, n4, n5, n6 and n7 are independently 0, 1, 2, 3, 4, 5 or 6;

[0026] m1 and m2 are independently 0, 1, 2, 3, 4 or 5;

[0027] Ring D is C3-C6 cycloalkane, 3-10 membered heterocycle in which "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3", C6-C 10 aromatic ring or a 5-10 membered heteroaromatic ring in which "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3";

[0028] R 3-1a is a ligand for E3 ligase, which structure can be, for example,

[0029] R 3-1a-1 and R 3-1a-2 are independently hydrogen, C1-C6 alkyl,

[0030] Ring A can be a 5-6 membered heterocycle in which "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2";

[0031] Ring B can be a C6-C 10 aromatic ring;

[0032] Ring C can be a 5-10 membered heteroaromatic ring in which "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3";

[0033] R a R b R c R d and R e independently can be hydrogen, hydroxyl or C1-C6 alkyl;

[0034] o1, o2 and o3 independently can be 0, 1, 2, 3 or 4;

[0035] R 4 is halogen, OCH3, OH, CN, CONH2 or COOH;

[0036] R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 independently is 1, 2, 3, 4 or 5, when 2, 3, 4 or 5, R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 independently are the same or different.

[0037] In one aspect of the present application, the compound of formula A is a compound of formula I or I',

[0038]

[0039] wherein the carbon atom marked with "*" is an S configuration carbon atom, an R configuration carbon atom or an achiral carbon atom; R 1 , R 2 , R 3 , R 4 and Z are as defined above.

[0040] In one aspect of the present application, the definition of some groups is as follows, and the definition of the groups not mentioned is the same as mentioned above (hereinafter referred to as in one aspect) : when R 5 is C1-C6 alkyl, the C1-C6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

[0041] In one aspect of the present application: is R 1 is C1-C6 alkyl; for example

[0042] In a certain embodiment of the application: when R 5 is unsubstituted or substituted C2-C6alkenyl, the number of R 5-5 may be 1, 2, or 3. 5-5

[0043] In a certain embodiment of the application: when R 5 is unsubstituted or substituted C2-C6alkenyl, the C2-C6alkenyl may be C2-C4alkenyl, preferably 5-5

[0044] In a certain embodiment of the application: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 , and R 5-7 are independently unsubstituted or substituted C1-C6alkyl, the number of R 5-1a may independently be 1, 2, or 3. 5-1a

[0045] In a certain embodiment: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 , and R 5-7 are independently unsubstituted or substituted C1-C6alkyl, the C1-C6alkyl may independently be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl, ethyl, or t-butyl. 5-1a

[0046] In a certain embodiment: when R 5-1 is unsubstituted or substituted C2-C6alkenyl, the number of R 5-2a may be 1, 2, or 3. 5-2a

[0047] In a certain embodiment: when R 5-1 is unsubstituted or substituted C2-C6alkenyl, the alkenyl may be C2-C4alkenyl, preferably ethenyl. 5-2a

[0048] In a certain embodiment: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 , and R 5-7 ​​​​​​independently C1-C6alkyl, the C1-C6alkyl can independently be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl.

[0049] In a certain embodiment: when R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-6 , and R 5-7 are independently C1-C6alkyl, the C1-C6alkyl can independently be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl.

[0050] In a certain embodiment: when R 5-5 is halogen, the halogen can be fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0051] In a certain embodiment: when R 5-1a is C1-C6alkoxy substituted or unsubstituted with R 5-1a-1 , the number of R 4-1a-1 can be 1, 2, or 3.

[0052] In a certain embodiment: when R 5-1a is C1-C6alkoxy substituted or unsubstituted with R 5-1a-1 , the C1-C6alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or t-butoxy, preferably methoxy or ethoxy.

[0053] In a certain embodiment: when R 5-1a-1 is C1-C6alkoxy, the C1-C6alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or t-butoxy, preferably methoxy.

[0054] In a certain embodiment: when R 5-2a is C1-C6alkyl, the C1-C6alkyl can independently be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl.

[0055] In a certain embodiment: when R 5-2a is halogen, the halogen can be fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0056] In a certain embodiment: when R 1 is C1-C6alkyl, the C1-C6alkyl can independently be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl.

[0057] In a certain embodiment: when R2 For R 2-2 Substituted or unsubstituted C6-C 15 When aryl, R 2-2 The number of them can be 1, 2, 3 or 4.

[0058] In a certain scheme: when R 2 For R 2-2 Substituted or unsubstituted C6-C 15 In the aryl case, the C6-C 15 Aryl groups can be C6-C 10 Aryl, preferably phenyl or naphthyl.

[0059] In a certain scheme: when R 2 For R 2-3 When the substituted or unsubstituted heteroaryl group is a 5-15 membered heteroaryl group selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4, R 2-3 The number of them can be 1, 2, 3 or 4.

[0060] In a certain scheme: when R 2 For R 2-3 When the substituted or unsubstituted 5-15-membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4, the 5-15-membered heteroaryl group selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 can be a 5-15-membered monocyclic heteroaryl or bicyclic heteroaryl group selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0061] The 5-15 membered monocyclic heteroaryl group described as having "heteroatoms selected from one or more of N, O, and S, with 1, 2, 3, or 4 heteroatoms" is preferably a 5-6 membered monocyclic heteroaryl group described as having "heteroatoms selected from N, with 1, 2, or 4 heteroatoms," and more preferably a pyridyl group (e.g., pyridyl group). ), or "the heteroatom is selected from N, and the number of heteroatoms is 1-2" of an 8-10 membered bicyclic heteroaryl group, preferably indazole group, for example

[0062] In a certain scheme: when R 2-1 For R 2-1a Substituted or unsubstituted C6-C 15 When aryl, R 2-1a The number of them can be 1, 2, 3 or 4.

[0063] In a certain scheme: when R 2-1 For R 2-1a Substituted or unsubstituted C6-C 15 In the aryl case, the C6-C 15Aryl groups can be C6-C 10 Aryl, preferably phenyl or naphthyl.

[0064] In a certain scheme: when R 2-2 When the halogen is halogen, it can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0065] In a certain scheme: when R 2-2 When the alkyl group is C1-C6, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0066] In a certain scheme: when R 2-2 When the alkoxy group is C1-C6, the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, with methoxy being preferred.

[0067] In a certain scheme: when R 2-1a When the halogen is halogen, it can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0068] In a certain scheme: when R 2-1a When the alkyl group is C1-C6, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0069] In a certain scheme: when R 2-1a When the alkoxy group is C1-C6, the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, with methoxy being preferred.

[0070] In a certain scheme: when R 2-2a For R 2-2a-1 When substituted or unsubstituted C1-C6 alkyl groups, R 2-2a-1 The number of them can be 1, 2 or 3.

[0071] In a certain scheme: when R 2-2a For R 2-2a-1 When the C1-C6 alkyl group is substituted or unsubstituted, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.

[0072] In a certain scheme: when R 2-2b For R 2-2a-1 When substituted or unsubstituted C1-C6 alkyl groups, R 2-2a-1 The number of them can be 1, 2 or 3.

[0073] In a certain scheme: when R 2-2b For R2-2a-1 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl.

[0074] In one embodiment: when R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 2-2a-1 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 2-2a-1a When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 2-2a-1a The number of R can be 1, 2, or 3.

[0075] In one embodiment: when R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 2-2a-1 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 2-2a-1a When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl.

[0076] In one embodiment: when R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 2-2a-1a When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl.

[0077] In one embodiment: when R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 3 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 3-1 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 15 The number of R can be 1, 2, 3, or 4. 3-1 The number of R can be 1, 2, 3, or 4.

[0078] In one embodiment: when R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 3 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 3-1 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 15 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 15 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 10 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl.

[0079] In one embodiment: when R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 3 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 3-2 The number of R can be 1, 2, 3, or 4. 3-2 The number of R can be 1, 2, 3, or 4.

[0080] In one embodiment: when R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 3 When R is substituted or unsubstituted C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl, preferably methyl or ethyl. 3-2In case of a substituted or unsubstituted "5-15 membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being 1, 2, 3 or 4", said "5-15 membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being 1, 2, 3 or 4" can be a "5-15 membered monocyclic or bicyclic heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being 1, 2, 3 or 4".

[0081] Said "5-15 membered monocyclic heteroaryl having one or more heteroatoms selected from the group consisting of N, O and S, the number of heteroatoms being 1, 2, 3 or 4" is preferably a "5-6 membered monocyclic heteroaryl having one or more heteroatoms selected from the group consisting of N, the number of heteroatoms being 1, 2 or 3", more preferably a pyridyl group (e.g. ).

[0082] In a certain embodiment: when R 3-1 is C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.

[0083] In a certain embodiment: when R 3-1 is C1-C6alkoxy, said C1-C6alkyl can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.

[0084] In a certain embodiment: when R 3-2 is C1-C6alkyl, said C1-C6alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.

[0085] In a certain embodiment: when R 3-2 is C1-C6alkoxy, said C1-C6alkyl can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.

[0086] In a certain embodiment: when ring D is C3-C6cycloalkane, said C3-C6cycloalkyl can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclohexane for example is ).

[0087] In one aspect, when ring D is a 3-10 membered heterocyclic ring having "one or more heteroatoms selected from N, O, and S, in an amount of 1-3", said 3-10 membered heterocyclic ring having "one or more heteroatoms selected from N, O, and S, in an amount of 1-3" can be a 3-6 membered heterocyclic ring having "one or more heteroatoms selected from N, O, and S, in an amount of 1-3", preferably tetrahydrofuran , for example , piperidine , for example , or piperazine , for example .

[0088] In one aspect, when ring D is a C6-C 10 aromatic ring, said C6-C 10 aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring , for example .

[0089] In one aspect, when ring D is a 5-10 membered heteroaromatic ring having "one or more heteroatoms selected from N, O, and S, in an amount of 1-3", said 5-10 membered heteroaromatic ring having "one or more heteroatoms selected from N, O, and S, in an amount of 1-3" can be a 5-6 membered heteroaromatic ring having "one or more heteroatoms selected from N, O, and S, in an amount of 1-3", preferably a pyridine ring , for example , or a pyrazine ring , for example .

[0090] In one aspect, when R 3-1a-1 is C1-C6 alkyl, said C1-C6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.

[0091] In one aspect, when R 3-1a-2 is C1-C6 alkyl, said C1-C6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.

[0092] In one aspect, in ring A, said 5-6 membered heterocycloalkyl having "one or more heteroatoms selected from N, O, and S, in an amount of 1-2" can be a 5-6 membered heterocycloalkyl having "one or more heteroatoms selected from N, in an amount of 1-2", preferably a tetrahydropyrrolyl , for example .

[0093] In one aspect, in ring B, said C6-C 10The aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring. For example, R ) can be

[0094] In one embodiment, the 5-10 membered heteroaromatic ring, wherein the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" in ring C can be a 5-10 membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring, wherein the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3".

[0095] The 5-10 membered monocyclic heteroaromatic ring, wherein the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3" is preferably a 5-6 membered monocyclic heteroaromatic ring, wherein the "heteroatoms are selected from one or more of N and S, and the number of heteroatoms is 1-2", more preferably a thiazole ring For example, R ) can be

[0096] In one embodiment, when R a , R b , R c , R d and R e are independently C1-C6 alkyl, the C1-C6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.

[0097] In one embodiment, when R 4 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.

[0098] In one embodiment, R 5 can be

[0099] In one embodiment, R 1 can be hydrogen or methyl.

[0100] In one embodiment, R can be

[0101] In one embodiment, R can be

[0102] In one embodiment, R can be

[0103] In one embodiment, R 2-2 and R 2-1aindependently can be -OH, -F, -Cl, -NH2, or -OMe.

[0104] In one aspect: R 2-1 may be

[0105] In one aspect: R 2 may be

[0106] In one aspect: -L- can be

[0107] In one aspect: R 3-1a may be

[0108] In one aspect: R 3-1 and R 3-2 independently can be OH, Me, Et, CN,

[0109] In one aspect: R 3 may be

[0110] In an embodiment, the E3 ligase is von Hippel-Lindau (VHL), CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP (pan), ITCH / AIP4, KAP1, MARCH8, Mind Bomb 1 / MIB1, Mind Bomb 2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3, preferably VHL, CRBN, MDM2, or cIAP.

[0111] In an embodiment, R 1 is F. 1 The configuration of the C atom to which R 4 is attached is the S configuration.

[0112] In an embodiment, R 4 is F.

[0113] In an embodiment, R 3 is

[0114] In one aspect, Z can be NR 5 .

[0115] In one aspect, R 5 may be

[0116] In one aspect, R 5 may be

[0117] In one aspect, R 5 may be

[0118] In one aspect, R 5-1 may be R 5-1a substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxy.

[0119] In one aspect, R 5-1 may be R 5-1a substituted or unsubstituted C1-C6 alkyl or C2-C6 alkenyl.

[0120] In one aspect, R 5-1 may be C2-C6 alkenyl.

[0121] In one aspect, R 5-2 may be C1-C6 alkyl.

[0122] In one aspect, R 5-3 and R 5-4 may be independently hydrogen, or R 5-1a substituted or unsubstituted C1-C6 alkyl.

[0123] In one aspect, R 1 may be hydrogen.

[0124] In one aspect, R 2 may be R 2-2 substituted or unsubstituted C6-C 15 aryl.

[0125] In one aspect, R 2 may be R 2-2 substituted C6-C 15 aryl.

[0126] In one aspect, R 2-2 may be hydroxyl, halogen, amino, or C1-C6 alkoxy.

[0127] In one aspect, R 2-2 may be hydroxyl, halogen, or amino.

[0128] In one aspect: R 2-2 may be hydroxy or halogen.

[0129] In one aspect: R 2-1a may be halogen.

[0130] In one aspect: R 3 may be C6-C 3-1 aryl, or a 5-15 membered heteroaryl having "one or more heteroatoms selected from the group consisting of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4," substituted with R 15 may be C6-C 3-2 aryl, or a 5-15 membered heteroaryl having "one or more heteroatoms selected from the group consisting of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4," substituted with R

[0131] In one aspect: R 3 may be a 5-15 membered heteroaryl having "one or more heteroatoms selected from the group consisting of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4," substituted with R 3-2 may be a 5-15 membered heteroaryl having "one or more heteroatoms selected from the group consisting of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4," substituted with R

[0132] In one aspect: R 3-1 and R 3-2 may be independently C1-C6 alkyl or -L-R 3-1a .

[0133] In one aspect: R 3-1 and R 3-2 may be independently C1-C6 alkyl.

[0134] In one aspect: R 3-1 and R 3-2 may be independently methyl or isopropyl.

[0135] In one aspect: -L- can be a terminus connected to R 3-1a and a terminus connected to C6-C 15 aryl or a 5-15 membered heteroaryl having "one or more heteroatoms selected from the group consisting of N, O, and S, the number of heteroatoms being 1, 2, 3, or 4."

[0136] In one aspect: n1 can be 0, 1, 2, 3, 4, 5, or 6.

[0137] In one aspect: m1 can be 0, 1, 2, or 3.

[0138] In one aspect: R 3-1a may be

[0139] In one aspect: R 3-1a-1 and R 3-1a-2 may be independently hydrogen or

[0140] In one aspect: R3-1 and R 3-2 The number of elements can be 2, and R 3-1 and R 3-2 different.

[0141] In one of the proposed solutions:

[0142] R 4 For F;

[0143] Z is NR 5 ;

[0144] R 5 for

[0145] R 5-1 For R 5-1a Substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxy groups;

[0146] R 5-2 It is a C1-C6 alkyl group;

[0147] R 5-3 and R 5-4 Independently hydrogen, or by R 5-1a Substituted or unsubstituted C1-C6 alkyl groups;

[0148] R 5-1a For R 5-1a-1 Substituted or unsubstituted C1-C6 alkoxy groups;

[0149] R 5-1a-1 It is a C1-C6 alkoxy group;

[0150] R 1 It is hydrogen or C1-C6 alkyl;

[0151] R 2 For R 2-2 Substituted or unsubstituted C6-C 15 Aryl;

[0152] R 2-2 It is a hydroxyl, halogen, amino, or C1-C6 alkoxy group;

[0153] R 3 For R 3-1 Substituted or unsubstituted C6-C 15 Aryl, or R 3-2 5-15-membered heteroaryl groups, with substituted or unsubstituted heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms being 1, 2, 3, or 4;

[0154] R 3-1 and R 3-2Independently C1-C6 alkyl or -LR 3-1a ;

[0155] -L- is a-end and R 3-1a Connected, end b is connected to C6-C 15 The aryl group or a 5-15 membered heteroaryl group, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4, is connected;

[0156] n1 is 0, 1, 2, 3, 4, 5 or 6;

[0157] m1 can be 0, 1, 2, or 3;

[0158] R 3-1a for

[0159] R 3-1a-1 and R 3-1a-2 Independently hydrogen or

[0160] In one of the proposed solutions:

[0161] R 4 For F;

[0162] Z is NR 5 ;

[0163] R 5 for

[0164] R 5-1 For R 5-1a Substituted or unsubstituted C1-C6 alkyl or C2-C6 alkenyl groups;

[0165] R 5-2 It is a C1-C6 alkyl group;

[0166] R 5-3 and R 5-4 Independently hydrogen, or by R 5-1a Substituted or unsubstituted C1-C6 alkyl groups;

[0167] R 5-1a For R 5-1a-1 Substituted or unsubstituted C1-C6 alkoxy groups;

[0168] R 5-1a-1 It is a C1-C6 alkoxy group;

[0169] R 1 It is hydrogen;

[0170] R 2 For R 2-2 Replacement C6-C15 Aryl;

[0171] R 2-2 It is a hydroxyl, halogen, amino, or C1-C6 alkoxy group;

[0172] R 3 For R 3-1 Substituted or unsubstituted C6-C 15 Aryl, or R 3-2 5-15-membered heteroaryl groups, with substituted or unsubstituted heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms being 1, 2, 3, or 4;

[0173] R 3-1 and R 3-2 It is independently a C1-C6 alkyl group.

[0174] In one of the proposed solutions:

[0175] R 4 For F;

[0176] Z is NR 5 ;

[0177] R 5 for

[0178] R 5-1 It is a C2-C6 alkenyl group;

[0179] R 1 It is hydrogen;

[0180] R 2 For R 2-2 Replacement C6-C 15 Aryl;

[0181] R 2-2 It is hydroxyl, halogen or amino;

[0182] R 3 For R 3-1 Replacement C6-C 15 Aryl, or R 3-2 The substituted heteroatoms are 5-15-membered heteroaryl groups selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0183] R 3-1 and R 3-2 Independently, it is a C1-C6 alkyl group;

[0184] R 3-1 and R 3-2 The number of elements is 2, and R 3-1 and R 3-2 different.

[0185] In one of the proposed solutions:

[0186] R 4 For F;

[0187] Z is NR 5 ;

[0188] R 5 for

[0189] R 5-1 It is a C2-C6 alkenyl group;

[0190] R 1 It is hydrogen;

[0191] R 2 For R 2-2 Replacement C6-C 15 Aryl;

[0192] R 2-2 It is a hydroxyl group or a halogen;

[0193] R 3 For R 3-1 Replacement C6-C 15 Aryl, or R 3-2 The substituted heteroatoms are 5-15-membered heteroaryl groups selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0194] R 3-1 and R 3-2 It can be methyl or isopropyl independently;

[0195] R 3-1 and R 3-2 The number of elements is 2, and R 3-1 and R 3-2 different.

[0196] In one of the proposed solutions:

[0197] R 4 For F;

[0198] Z is NR 5 ;

[0199] R 5 for

[0200] R 5-1 It is a C2-C6 alkenyl group;

[0201] R 1 It is hydrogen;

[0202] R 2 For R2-2 substituted C6-Ci0aryl; 15 substituted C6-Ci0aryl;

[0203] R 2-2 is hydroxyl or halogen;

[0204] R 3 is C1-C6alkyl. 3-2 substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15 membered heteroaryl;

[0205] R 3-2 is C1-C6alkyl.

[0206] In the present application, the compound as shown in formula I can be any one of the following structures,

[0207]

[0208] In the present application, the compound as shown in formula I' can be any one of the following structures,

[0209]

[0210] The present application provides a preparation method of the compound as shown in formula A, which is method one, method two, method three or method four,

[0211] Method one comprises the following steps: in the presence of a base, a compound as shown in formula II-1A and a compound as shown in formula II-2 are subjected to the following reaction in a solvent to obtain the compound as shown in formula A,

[0212]

[0213] For example, when formula A is formula I, method one comprises the following steps: in the presence of a base, a compound as shown in formula II-1 and a compound as shown in formula II-2 are subjected to the following reaction in a solvent to obtain the compound as shown in formula I,

[0214]

[0215] Method two comprises the following steps: in the presence of a base and a catalyst, a compound as shown in formula III-1A and a compound as shown in formula III-2 or III-3 are subjected to the following reaction in a solvent to obtain the compound as shown in formula A,

[0216]

[0217] For example, when Formula A is Formula I, Method Two comprises the step of reacting a compound of Formula III-1 and a compound of Formula III-2 or III-3 in a solvent in the presence of a base and a catalyst as shown below to yield the compound of Formula I.

[0218]

[0219] In Method One or Method Two, Z is NR 5 , R 5 is

[0220] Method Three comprises the step of reacting a compound of Formula IV-1A and IV-2 in a solvent in the presence of a base as shown below to yield the compound of Formula A.

[0221]

[0222] For example, when Formula A is Formula I, Method Three comprises the step of reacting a compound of Formula IV-1 and IV-2 in a solvent in the presence of a base as shown below to yield the compound of Formula I.

[0223]

[0224] In Method Three, Z is NR 5 , R 5 is

[0225] Method Four comprises the step of reacting a compound of Formula V-1A and a compound of Formula V-2 or V-3 in a solvent in the presence of a base and a catalyst as shown below to yield the compound of Formula A.

[0226]

[0227] For example, when Formula A is Formula I, Method Four comprises the step of reacting a compound of Formula V-1 and a compound of Formula V-2 or V-3 in a solvent in the presence of a base and a catalyst as shown below to yield the compound of Formula I.

[0228]

[0229] In Method Four, Z is O or NR 5 , R 5 is C1-C6 alkyl;

[0230] wherein R 1 , R 2 , R 3 , R4 R 5-1 R 5-3 R 5-4 R

[0231] In one embodiment, the reaction conditions and procedures of Method One, Method Two, Method Three or Method Four are the same as the conventional reaction conditions and procedures in the art.

[0232] The present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0233] In one embodiment, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0234] The pharmaceutically acceptable carrier can include a pharmaceutically acceptable carrier, diluent and / or excipient.

[0235] The pharmaceutical composition can be in a form of a tablet, a pill, a powder, a liquid, a suspension, an emulsion, a granule, a capsule, a suppository, a needle (solution and suspension), etc. according to the purpose of treatment, and preferably in a form of a liquid, a suspension, an emulsion, a suppository, a needle (solution and suspension), etc.

[0236] For the formation of the pharmaceutical composition in a form of a tablet, any known and widely used excipient in the art can be used. For example, a carrier such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.; a binder such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinyl pyrrolidone, etc.; a disintegrant such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid ester of polyethylene sorbitan, sodium dodecyl sulfate, stearic acid monoglyceride, starch and lactose, etc.; a disintegration inhibitor such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; an adsorption accelerator such as a quaternary amine base and sodium dodecyl sulfate, etc.; a wetting agent such as glycerol, starch, etc.; an adsorbent such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; and a lubricant such as pure talc, stearate, boric acid powder and polyethylene glycol, etc. can be used. Also, a common coating material can be selected as needed to form a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double film-coated tablet and a multi-layer tablet.

[0237] To shape the pharmaceutical composition in the form of a pill, any known and widely used excipient in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders such as acacia powder, tragacanth powder, gelatin and ethanol, etc.; disintegrants such as agar and kelp powder, etc.

[0238] To shape the pharmaceutical composition in the form of a suppository, any known and widely used excipient in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohol, ester of higher alcohol, gelatin and semi-synthetic glyceride, etc.

[0239] To prepare the pharmaceutical composition in the form of an injection, a solution or suspension is sterilized (preferably, an appropriate amount of sodium chloride, glucose or glycerol, etc. is added) to make an injection isotonic with blood. In preparing the injection, any commonly used carrier in the art can be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid ester of polyethylene sorbitan, etc. In addition, a common dissolving agent, buffer and analgesic, etc. can be added.

[0240] In the present application, the content of the compound in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and generally can be 5 to 95% by mass, and preferably 30 to 80% by mass.

[0241] In the present application, the method of administering the pharmaceutical composition is not particularly limited. Various dosage forms of preparations can be administered according to the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or mixed with a delivery solution for injection (e.g., glucose solution and amino acid solution) for intravenous injection; and suppositories are administered to the rectum.

[0242] This invention provides the use of the compound shown in Formula A or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a KRAS inhibitor, wherein the KRAS inhibitor is preferably a KRAS G12C inhibitor. The KRAS inhibitor is used in vitro. In one embodiment, this invention provides the use of the compound shown in Formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a KRAS inhibitor, wherein the KRAS inhibitor is preferably a KRAS G12C inhibitor. The KRAS inhibitor is used in vitro. This invention provides the use of the compound shown in Formula A or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of KRAS-related diseases. KRAS is preferably KRAS G12C. In one embodiment, this invention provides the use of the compound shown in Formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of KRAS-related diseases. KRAS is preferably KRAS G12C. The KRAS-related diseases mentioned above can be cancers characterized by KRAS mutations, such as pancreatic cancer, colorectal cancer, or lung adenocarcinoma.

[0243] This invention provides the use of the compound shown in Formula A above, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the preparation of a medicament for the prevention and / or treatment of cancer. In one embodiment, this invention provides the use of the compound shown in Formula I above, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the preparation of a medicament for the prevention and / or treatment of cancer. The cancer may be a cancer characterized by KRAS mutations, such as pancreatic cancer, colorectal cancer, or lung adenocarcinoma.

[0244] This invention provides a compound of formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystal form, or its solvate.

[0245]

[0246] in,

[0247] Z is O or NR 5 ;

[0248] R 5 C1-C6 alkyl, R 5-5 Substituted or unsubstituted C2-C6 alkenyl groups

[0249] R 5-1 R 5-2 R5-3 R 5-4 R 5-6 and R 5-7 Independently hydrogen, by R 5-1a Substituted or unsubstituted C1-C6 alkyl groups, R 5 -2a Substituted or unsubstituted C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy groups;

[0250] R 5-5 It is either cyano or halogen;

[0251] R 5-1a For R 5-1a-1 Substituted or unsubstituted C1-C6 alkoxy groups;

[0252] R 5-1a-1 It is a C1-C6 alkoxy group;

[0253] R 5-2a It is a C1-C6 alkyl, cyano, or halogen;

[0254] R 1 It is hydrogen or C1-C6 alkyl;

[0255] R 2 OR 2-1 、Being R 2-2 Substituted or unsubstituted C6-C 15 Aryl or R 2-3 5-15-membered heteroaryl groups, with substituted or unsubstituted heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms being 1, 2, 3, or 4;

[0256] R 2-1 For R 2-1a Substituted or unsubstituted C6-C 15 Aryl;

[0257] R 2-2 R 2-3 and R 2-1a Independently hydroxyl, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy,

[0258] R 2-2a and R 2-2b Independently for R 2-2a-1 Substituted or unsubstituted C1-C6 alkyl groups;

[0259] R 2-2a-1 For R 2-2a-1a Substituted or unsubstituted C1-C6 alkoxy groups;

[0260] R 2-2a-1aC1-C6alkoxy;

[0261] R 3 is a ligand for E3 ligase, which can have a structure such as 3-1 substituted or unsubstituted C6-C 15 aryl, or 5-15 membered heteroaryl substituted or unsubstituted with R 3-2 substituted or unsubstituted "heteroatoms selected from one or more of N, O, and S, in a number ranging from 1, 2, 3, or 4";

[0262] R 3-1 and R 3-2 are independently hydroxyl, cyano, amino, halogen, C1-C6alkyl, C1-C6alkoxy, -L-R 3-1a ;

[0263] -L- is a is attached at the end to R 3-1a and b is attached at the end to C6-C 15 aryl or 5-15 membered heteroaryl "heteroatoms selected from one or more of N, O, and S, in a number ranging from 1, 2, 3, or 4";

[0264] n1, n2, n3, n4, n5, n6, and n7 are independently 0, 1, 2, 3, 4, 5, or 6;

[0265] m1and m2are independently 0, 1, 2, 3, 4, or 5;

[0266] Ring D is C3-C6cycloalkane, 3-10 membered heterocycle "heteroatoms selected from one or more of N, O, and S, in a number ranging from 1-3", C6-C 10 aromatic ring, or 5-10 membered heteroaromatic ring "heteroatoms selected from one or more of N, O, and S, in a number ranging from 1-3";

[0267] R 3-1a is a ligand for E3 ligase, which can have a structure such as

[0268] R 3-1a-1 and R 3-1a-2 are independently hydrogen, C1-C6alkyl,

[0269] Ring A can be 5-6 membered heterocycle "heteroatoms selected from one or more of N, O, and S, in a number ranging from 1-2";

[0270] Ring B can be C6-C 10 aromatic ring;

[0271] Ring C can be a 5-10 membered heteroaromatic ring, "the number of heteroatoms is 1-3, the heteroatoms are selected from one or more of N, O and S";

[0272] R a , R b , R c , R d and R e independently can be hydrogen, hydroxyl or C1-C6 alkyl;

[0273] o1, o2and o3independently can be 0, 1, 2, 3 or 4;

[0274] R 4 is halogen, OCH3, OH, CN, CONH2or COOH;

[0275] R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 independently can be 1, 2, 3, 4 or 5, when being 2, 3, 4 or 5, R 5-1a , R 5-1a-1 , R 2-2 , R 2-1a , R 2-2a-1 , R 2-2a-1a , R 3-1 and R 3-2 independently are the same or different.

[0276] In one aspect of the present application, the compound of formula A is a compound of formula I or I',

[0277]

[0278] wherein R 1 , R 2 , R 3 , R 4 , Z and * are as defined above.

[0279] In one aspect of the present application, the definition of some groups is as follows, the groups not defined are the same as defined above (hereinafter referred to as in one aspect): when R 5 is C1-C6 alkyl, the C1-C6 alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

[0280] In one aspect of the present application: when R 5 is R 5-5When the C2-C6 alkenyl group is substituted or unsubstituted, the R 5-5 The number of them can be 1, 2 or 3.

[0281] In one aspect of this invention: when R 5 For R 5-5 When the C2-C6 alkenyl group is substituted or unsubstituted, the C2-C6 alkenyl group can be a C2-C4 alkenyl group, preferably.

[0282] In one aspect of this invention: when R 5-1 R 5-2 R 5-3 R 5-4 R 5-6 and R 5-7 Independently for R 5-1a When substituted or unsubstituted C1-C6 alkyl groups, R 5-1a The number of elements can be 1, 2, or 3 independently.

[0283] In a certain scheme: when R 5-1 R 5-2 R 5-3 R 5-4 R 5-6 and R 5-7 Independently for R 5-1a When the C1-C6 alkyl group is substituted or unsubstituted, the C1-C6 alkyl group may be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or tert-butyl.

[0284] In a certain scheme: when R 5-1 For R 5-2a When the C2-C6 alkenyl group is substituted or unsubstituted, the R 5-2a The number of them can be 1, 2 or 3.

[0285] In a certain scheme: when R 5-1 For R 5-2a When the C2-C6 alkenyl group is substituted or unsubstituted, the alkenyl group may be a C2-C4 alkenyl group, preferably a vinyl group.

[0286] In a certain scheme: when R 5-1 R 5-2 R 5-3 R 5-4 R 5-6 and R 5-7 When independently of a C2-C6 ynyl group, the C2-C6 ynyl group can be a C2-C4 ynyl group, preferably an acetyl group.

[0287] In a certain scheme: when R 5-1 R5-2 R 5-3 R 5-4 R 5-6 and R 5-7 When independently C1-C6 alkoxy, the C1-C6 alkoxy may be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, preferably methoxy.

[0288] In a certain scheme: when R 5-5 When the halogen is halogen, it can be fluorine, chlorine, bromine or iodine, with fluorine being preferred.

[0289] In a certain scheme: when R 5-1a For R 5-1a-1 When substituted or unsubstituted C1-C6 alkoxy groups, R 4-1a-1 The number of them can be 1, 2 or 3.

[0290] In a certain scheme: when R 5-1a For R 5-1a-1 When the C1-C6 alkoxy group is substituted or unsubstituted, the C1-C6 alkoxy group may be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, preferably methoxy or ethoxy.

[0291] In a certain scheme: when R 5-1a-1 When the alkoxy group is C1-C6, the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, with methoxy being preferred.

[0292] In a certain scheme: when R 5-2a When the alkyl group is C1-C6, the C1-C6 alkyl group can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

[0293] In a certain scheme: when R 5-2a When the halogen is halogen, it can be fluorine, chlorine, bromine or iodine, with fluorine being preferred.

[0294] In a certain scheme: when R 1 When the alkyl group is C1-C6, the C1-C6 alkyl group can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

[0295] In a certain scheme: when R 2 For R 2-2 Substituted or unsubstituted C6-C 15 When aryl, R 2-2 The number of them can be 1, 2, 3 or 4.

[0296] In a certain scheme: when R 2 For R 2-2 Substituted or unsubstituted C6-C 15 In the aryl case, the C6-C 15 Aryl groups can be C6-C 10 Aryl, preferably phenyl or naphthyl.

[0297] In a certain scheme: when R 2 For R 2-3 When the substituted or unsubstituted heteroaryl group is a 5-15 membered heteroaryl group selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4, R 2-3 The number of them can be 1, 2, 3 or 4.

[0298] In a certain scheme: when R 2 For R 2-3 When the substituted or unsubstituted 5-15-membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4, the 5-15-membered heteroaryl group selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 can be a 5-15-membered monocyclic heteroaryl or bicyclic heteroaryl group selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0299] The 5-15 membered monocyclic heteroaryl group described as having "heteroatoms selected from one or more of N, O, and S, with 1, 2, 3, or 4 heteroatoms" is preferably a 5-6 membered monocyclic heteroaryl group described as having "heteroatoms selected from N, with 1, 2, or 4 heteroatoms," and more preferably a pyridyl group (e.g., pyridyl group). ), or "the heteroatom is selected from N, and the number of heteroatoms is 1-2" of an 8-10 membered bicyclic heteroaryl group, preferably indazole group, for example

[0300] In a certain scheme: when R 2-1 For R 2-1a Substituted or unsubstituted C6-C 15 When aryl, R 2-1a The number of them can be 1, 2, 3 or 4.

[0301] In a certain scheme: when R 2-1 For R 2-1a Substituted or unsubstituted C6-C 15 In the aryl case, the C6-C 15 Aryl groups can be C6-C 10 Aryl, preferably phenyl or naphthyl.

[0302] In a certain scheme: when R 2-2When the halogen is halogen, it can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0303] In a certain scheme: when R 2-2 When the alkyl group is C1-C6, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0304] In a certain scheme: when R 2-2 When the alkoxy group is C1-C6, the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, with methoxy being preferred.

[0305] In a certain scheme: when R 2-1a When the halogen is halogen, it can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0306] In a certain scheme: when R 2-1a When the alkyl group is C1-C6, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0307] In a certain scheme: when R 2-1a When the alkoxy group is C1-C6, the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, with methoxy being preferred.

[0308] In a certain scheme: when R 2-2a For R 2-2a-1 When substituted or unsubstituted C1-C6 alkyl groups, R 2-2a-1 The number of them can be 1, 2 or 3.

[0309] In a certain scheme: when R 2-2a For R 2-2a-1 When the C1-C6 alkyl group is substituted or unsubstituted, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.

[0310] In a certain scheme: when R 2-2b For R 2-2a-1 When substituted or unsubstituted C1-C6 alkyl groups, R 2-2a-1 The number of them can be 1, 2 or 3.

[0311] In a certain scheme: when R 2-2b For R 2-2a-1 When the C1-C6 alkyl group is substituted or unsubstituted, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.

[0312] In a certain scheme: when R 2-2a-1 For R 2-2a-1a When substituted or unsubstituted C1-C6 alkoxy groups, R 2-2a-1a The number of them can be 1, 2 or 3.

[0313] In a certain scheme: when R 2-2a-1 For R 2-2a-1a When the C1-C6 alkoxy group is substituted or unsubstituted, the C1-C6 alkoxy group may be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, preferably methoxy or ethoxy.

[0314] In a certain scheme: when R 2-2a-1a When the alkoxy group is C1-C6, the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, with methoxy being preferred.

[0315] In a certain scheme: when R 3 For R 3-1 Substituted or unsubstituted C6-C 15 When aryl, R 3-1 The number of them can be 1, 2, 3 or 4.

[0316] In a certain scheme: when R 3 For R 3-1 Substituted or unsubstituted C6-C 15 In the aryl case, the C6-C 15 Aryl groups can be C6-C 10 Aryl, preferably phenyl or naphthyl.

[0317] In a certain scheme: when R 3 For R 3-2 When the substituted or unsubstituted heteroaryl group is a 5-15 membered heteroaryl group selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4, R 3-2 The number of them can be 1, 2, 3 or 4.

[0318] In a certain scheme: when R 3 For R 3-2 When the substituted or unsubstituted 5-15-membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4, the 5-15-membered heteroaryl group selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 can be a 5-15-membered monocyclic heteroaryl or bicyclic heteroaryl group selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0319] The 5-15 membered monocyclic heteroaryl group wherein "the number of heteroatoms is one, two, three or four, and the heteroatoms are selected from one or more of N, O and S" is preferably a 5-6 membered monocyclic heteroaryl group wherein "the number of heteroatoms is one, two or three, and the heteroatoms are selected from N", more preferably a pyridyl group (e.g. ).

[0320] In one aspect, when R 3-1 is C1-C6 alkyl, the C1-C6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl, preferably methyl, ethyl or isopropyl.

[0321] In one aspect, when R 3-1 is C1-C6 alkoxy, the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy, preferably methoxy.

[0322] In one aspect, when R 3-2 is C1-C6 alkyl, the C1-C6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl, preferably methyl, ethyl or isopropyl.

[0323] In one aspect, when R 3-2 is C1-C6 alkoxy, the C1-C6 alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy, preferably methoxy.

[0324] In one aspect, when ring D is C3-C6 cycloalkane, the C3-C6 cycloalkane can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclohexane (e.g. ).

[0325] In one aspect, when ring D is a 3-10 membered heterocycle wherein "the number of heteroatoms is one to three, and the heteroatoms are selected from one or more of N, O and S", the 3-10 membered heterocycle wherein "the number of heteroatoms is one to three, and the heteroatoms are selected from one or more of N, O and S" can be a 3-6 membered heterocycle wherein "the number of heteroatoms is one to three, and the heteroatoms are selected from one or more of N, O and S", preferably tetrahydrofuran (e.g. ), piperidine (e.g. ), or piperazine (e.g. ).

[0326] In one aspect, when ring D is C6-C 10When aromatic rings are used, the C6-C 10 The aromatic ring can be a benzene ring or a naphthalene ring, with a benzene ring being preferred. For example, ).

[0327] In one embodiment: when ring D is a 5-10 membered heteroaromatic ring with "heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1-3", the 5-10 membered heteroaromatic ring with "heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1-3" can be a 5-6 membered heteroaromatic ring with "heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1-3", preferably a pyridine ring ( For example, ) or pyrazine ring ( For example, for example ).

[0328] In a certain scheme: when R 3-1a-1 When the alkyl group is C1-C6, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0329] In a certain scheme: when R 3-1a-2 When the alkyl group is C1-C6, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0330] In one embodiment: in ring A, the 5-6 membered heterocyclic alkyl group "selected from one or more of N, O, and S, with 1-2 heteroatoms" can be a 5-6 membered heterocyclic alkyl group "selected from N, with 1-2 heteroatoms", preferably tetrahydropyrrole ( For example, ).

[0331] In one scheme: in ring B, the C6-C 10 The aromatic ring can be a benzene ring or a naphthalene ring, with a benzene ring being preferred. For example, ).

[0332] In one embodiment: In ring C, the 5-10 membered heteroaromatic ring, in which "the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3", can be a 5-10 membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring, in which "the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3".

[0333] The 5-10 membered monocyclic heteroaromatic ring with "the heteroatoms being one or more selected from N, O and S, the number of heteroatoms being 1-3" is preferably a 5-6 membered monocyclic heteroaromatic ring with "the heteroatoms being one or more selected from N and S, the number of heteroatoms being 1-2", more preferably a thiazole ring. For example, R ) is methyl.

[0334] In one aspect, R a , R b , R c , R d and R e are independently C1-C6 alkyl.

[0335] In one aspect, R 4 is halogen.

[0336] In one aspect, R 5 is

[0337] In one aspect, R 1 is hydrogen or methyl.

[0338] In one aspect, R is

[0339] In one aspect, R is

[0340] In one aspect, R is

[0341] In one aspect, R 2-2 and R 2-1a are independently -OH, -F, -Cl, -NH2 or -OMe.

[0342] In one aspect, R 2-1 is

[0343] In one aspect, R 2 is

[0344] In one aspect, -L- is

[0345] In one aspect: R 3-1a may be

[0346] In one aspect: R 3-1 and R 3-2 independently can be OH, Me, Et, CN,

[0347] In one aspect: R 3 may be

[0348] In certain embodiments: the E3 ligase can be von Hippel-Lindau (VHL), CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP (pan), ITCH / AIP4, KAP1, MARCH8, Mind Bomb 1 / MIB1, Mind Bomb 2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3, preferably VHL, CRBN, MDM2, or cIAP.

[0349] In certain embodiments: R 1 is F. 1 The configuration of the C atom to which R 4 is attached is the S configuration.

[0350] In certain embodiments: R 4 is F.

[0351] In certain embodiments: R 3 is

[0352] In one aspect, Z can be NR 5 .

[0353] In one aspect, R 5 may be

[0354] In one aspect, R 5 may be

[0355] In one aspect, R 5 may be

[0356] In one aspect, R 5-1 may be R 5-1a substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxy.

[0357] In one aspect, R 5-1 may be R 5-1a substituted or unsubstituted C1-C6 alkyl or C2-C6 alkenyl.

[0358] In one aspect, R 5-1 may be C2-C6 alkenyl.

[0359] In one aspect, R 5-2 may be C1-C6 alkyl.

[0360] In one aspect, R 5-3 and R 5-4 may be independently hydrogen, or R 5-1a substituted or unsubstituted C1-C6 alkyl.

[0361] In one aspect, R 1 may be hydrogen.

[0362] In one aspect, R 2 may be R 2-2 substituted or unsubstituted C6-C 15 aryl.

[0363] In one aspect, R 2 may be R 2-2 substituted C6-C 15 aryl.

[0364] In one aspect, R 2-2 may be hydroxyl, halogen, amino, or C1-C6 alkoxy.

[0365] In one aspect, R 2-2 may be hydroxyl, halogen, or amino.

[0366] In one particular scheme: R 2-2 It can be hydroxyl or halogen.

[0367] In one particular scheme: R 2-1a It can be halogen.

[0368] In one particular scheme: R 3 Can be R 3-1 Replacement C6-C 15 Aryl, or R 3-2 The substituted heteroaryl group is a 5-15 membered heteroaryl group whose heteroatoms are selected from one or more of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4.

[0369] In one particular scheme: R 3 Can be R 3-2 The substituted heteroaryl group is a 5-15 membered heteroaryl group whose heteroatoms are selected from one or more of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4.

[0370] In one particular scheme: R 3-1 and R 3-2 It can be independently a C1-C6 alkyl or -LR 3-1a .

[0371] In one particular scheme: R 3-1 and R 3-2 It can be independently a C1-C6 alkyl group.

[0372] In one particular scheme: R 3-1 and R 3-2 It can be methyl or isopropyl independently.

[0373] In one particular scheme: -L- can be a-end and R 3-1a Connected, end b is connected to C6-C 15 The aryl group or a 5-15 membered heteroaryl group, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4, is connected.

[0374] In a certain scheme: n1 can be 0, 1, 2, 3, 4, 5 or 6.

[0375] In a given scheme: m1 can be 0, 1, 2 or 3.

[0376] In one particular scheme: R 3-1a Can be

[0377] In one particular scheme: R 3-1a-1 and R 3-1a-2 Independently can be hydrogen or

[0378] In one particular scheme: R3-1 and R 3-2 The number of elements can be 2, and R 3-1 and R 3-2 different.

[0379] In one of the proposed solutions:

[0380] R 4 For F;

[0381] Z is NR 5 ;

[0382] R 5 for

[0383] R 5-1 For R 5-1a Substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxy groups;

[0384] R 5-2 It is a C1-C6 alkyl group;

[0385] R 5-3 and R 5-4 Independently hydrogen, or by R 5-1a Substituted or unsubstituted C1-C6 alkyl groups;

[0386] R 5-1a For R 5-1a-1 Substituted or unsubstituted C1-C6 alkoxy groups;

[0387] R 5-1a-1 It is a C1-C6 alkoxy group;

[0388] R 1 It is hydrogen or C1-C6 alkyl;

[0389] R 2 For R 2-2 Substituted or unsubstituted C6-C 15 Aryl;

[0390] R 2-2 It is a hydroxyl, halogen, amino, or C1-C6 alkoxy group;

[0391] R 3 For R 3-1 Substituted or unsubstituted C6-C 15 Aryl, or R 3-2 5-15-membered heteroaryl groups, with substituted or unsubstituted heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms being 1, 2, 3, or 4;

[0392] R 3-1 and R 3-2Independently C1-C6 alkyl or -LR 3-1a ;

[0393] -L- is a-end and R 3-1a Connected, end b is connected to C6-C 15 The aryl group or a 5-15 membered heteroaryl group, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4, is connected;

[0394] n1 is 0, 1, 2, 3, 4, 5 or 6;

[0395] m1 can be 0, 1, 2, or 3;

[0396] R 3-1a for

[0397] R 3-1a-1 and R 3-1a-2 Independently hydrogen or

[0398] In one of the proposed solutions:

[0399] R 4 For F;

[0400] Z is NR 5 ;

[0401] R 5 for

[0402] R 5-1 For R 5-1a Substituted or unsubstituted C1-C6 alkyl or C2-C6 alkenyl groups;

[0403] R 5-2 It is a C1-C6 alkyl group;

[0404] R 5-3 and R 5-4 Independently hydrogen, or by R 5-1a Substituted or unsubstituted C1-C6 alkyl groups;

[0405] R 5-1a For R 5-1a-1 Substituted or unsubstituted C1-C6 alkoxy groups;

[0406] R 5-1a-1 It is a C1-C6 alkoxy group;

[0407] R 1 It is hydrogen;

[0408] R 2 For R 2-2 Replacement C6-C15 Aryl;

[0409] R 2-2 It is a hydroxyl, halogen, amino, or C1-C6 alkoxy group;

[0410] R 3 For R 3-1 Substituted or unsubstituted C6-C 15 Aryl, or R 3-2 5-15-membered heteroaryl groups, with substituted or unsubstituted heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms being 1, 2, 3, or 4;

[0411] R 3-1 and R 3-2 It is independently a C1-C6 alkyl group.

[0412] In one of the proposed solutions:

[0413] R 4 For F;

[0414] Z is NR 5 ;

[0415] R 5 for

[0416] R 5-1 It is a C2-C6 alkenyl group;

[0417] R 1 It is hydrogen;

[0418] R 2 For R 2-2 Replacement C6-C 15 Aryl;

[0419] R 2-2 It is hydroxyl, halogen or amino;

[0420] R 3 For R 3-1 Replacement C6-C 15 Aryl, or R 3-2 The substituted heteroatoms are 5-15-membered heteroaryl groups selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0421] R 3-1 and R 3-2 Independently, it is a C1-C6 alkyl group;

[0422] R 3-1 and R 3-2 The number of elements is 2, and R 3-1 and R 3-2 different.

[0423] In one of the proposed solutions:

[0424] R 4 For F;

[0425] Z is NR 5 ;

[0426] R 5 for

[0427] R 5-1 It is a C2-C6 alkenyl group;

[0428] R 1 It is hydrogen;

[0429] R 2 For R 2-2 Replacement C6-C 15 Aryl;

[0430] R 2-2 It is a hydroxyl group or a halogen;

[0431] R 3 For R 3-1 Replacement C6-C 15 Aryl, or R 3-2 The substituted heteroatoms are 5-15-membered heteroaryl groups selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0432] R 3-1 and R 3-2 It can be methyl or isopropyl independently;

[0433] R 3-1 and R 3-2 The number of elements is 2, and R 3-1 and R 3-2 different.

[0434] In one of the proposed solutions:

[0435] R 4 For F;

[0436] Z is NR 5 ;

[0437] R 5 for

[0438] R 5-1 It is a C2-C6 alkenyl group;

[0439] R 1 It is hydrogen;

[0440] R 2 For R2-2 substituted C6-Ci2aryl; 15 substituted C6-Ci2aryl;

[0441] R 2-2 is hydroxyl or halogen;

[0442] R 3 is C1-C6alkyl. 3-2 substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15 membered heteroaryl;

[0443] R 3-2 is C1-C6alkyl.

[0444] The present application provides a pharmaceutical composition comprising a compound of Formula A or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient; the compound of Formula A or a pharmaceutically acceptable salt thereof can be in a therapeutically effective amount.

[0445] In an embodiment, the present application provides a pharmaceutical composition comprising a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopologue thereof, a nitroxide thereof, a metabolite thereof, a prodrug thereof, a crystal form thereof, or a solvate thereof, and a pharmaceutical excipient. The compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopologue thereof, a nitroxide thereof, a metabolite thereof, a prodrug thereof, a crystal form thereof, or a solvate thereof can be in a therapeutically effective amount.

[0446] In the pharmaceutical composition, the pharmaceutical excipient can comprise a pharmaceutically acceptable carrier, diluent and / or excipient.

[0447] The present application provides use of a compound of Formula A, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopologue thereof, a nitroxide thereof, a metabolite thereof, a prodrug thereof, a crystal form thereof, or a solvate thereof, or a pharmaceutical composition thereof, in the manufacture of a kinase modulator. In an embodiment, the present application provides use of a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopologue thereof, a nitroxide thereof, a metabolite thereof, a prodrug thereof, a crystal form thereof, or a solvate thereof, or a pharmaceutical composition thereof, in the manufacture of a kinase modulator. The kinase modulator can be a kinase inhibitor or a kinase agonist. The kinase can be KRAS, for example KRAS G12C. The KRAS inhibitor is used in vitro.

[0448] The present application provides a use of a compound as shown in Formula A, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic compound thereof, a nitroxide thereof, a metabolite thereof, a prodrug thereof, a crystal form thereof, or a solvate thereof, or a pharmaceutical composition thereof in the manufacture of a medicament. In an aspect, the present application provides a use of a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic compound thereof, a nitroxide thereof, a metabolite thereof, a prodrug thereof, a crystal form thereof, or a solvate thereof, or a pharmaceutical composition thereof in the manufacture of a medicament. The medicament can be a medicament for preventing and / or treating a KRAS related disease or a medicament for preventing and / or treating a cancer. The KRAS is preferably KRAS G12C. The KRAS related disease can be a cancer. The cancer can be lung cancer, pancreatic cancer, pancreatic ductal carcinoma, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous carcinoma, head and neck squamous carcinoma, or breast cancer. The cancer can be a cancer characterized by KRAS mutation.

[0449] The present application also provides a method for treating a KRAS related disease, comprising administering to a patient a therapeutically effective amount of a compound as shown in Formula A, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic compound thereof, a nitroxide thereof, a metabolite thereof, a prodrug thereof, a crystal form thereof, or a solvate thereof, or a pharmaceutical composition thereof. In an aspect, the present application also provides a method for treating a KRAS related disease, comprising administering to a patient a therapeutically effective amount of a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic compound thereof, a nitroxide thereof, a metabolite thereof, a prodrug thereof, a crystal form thereof, or a solvate thereof, or a pharmaceutical composition thereof. The KRAS is preferably KRAS G12C. The KRAS related disease can be a cancer. The cancer can be lung cancer, pancreatic cancer, pancreatic ductal carcinoma, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous carcinoma, head and neck squamous carcinoma, or breast cancer. The cancer can be a cancer characterized by KRAS mutation.

[0450] KRAS mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to administering a disclosed compound (e.g., in the form of a pharmaceutical composition) to a patient in need of treatment for a hematological malignancy. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the presently disclosed compounds can be used to treat diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds can be used to treat lymphomas, such as Hodgkin’s lymphoma or non-Hodgkin’s lymphoma of all subtypes. In various embodiments, the compounds can be used to treat plasma cell malignancies, such as multiple myeloma, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia.

[0451] As used herein, the terms have the following meanings, unless indicated otherwise:

[0452] The term "pharmaceutically acceptable" means that the salt, solvent, adjuvant, etc. is not toxic or safe and suitable for use with patients. The "patient" is preferably a mammal, more preferably a human.

[0453] If stereoisomers exist in the substituents R1, R2, R3and R4in the "compound", "pharmaceutically acceptable salt", "tautomers", "isotopic compounds" or "solvate" of the present application, they can exist in the form of a single stereoisomer or a mixture thereof (e.g. racemate). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution through bonding (chemical combination, etc.) or salification (physical combination, etc.) with other chiral compounds. The term "single stereoisomer" refers to the mass content of one stereoisomer of the compound of the present application relative to all stereoisomers of the compound is not less than 95%.

[0454] The term "pharmaceutically acceptable salt" as used herein refers to those salts which are substantially non-toxic and which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio, as discussed in Berge, et al., "Pharmaceutically Acceptable Salts", J. Pharm. Sci., 66, 1-19 (1977), and are apparent to those skilled in the art. Such salts include, but are not limited to, salts of acids such as hydrochloric, hydrobromic, sulfuric, bisulfatic, bisulfate, sulfite, bisulfite, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, metaphosphoric, pyrophosphoric, nitric, acetic, propionic, decanoic, octanoic, formic, acrylate, isobutyric, hexanoic, heptanoic, oxalic, malonic, succinic, suberic, benzoic, methylbenzoic, phthalic, maleic, methanesulfonic, p-toluenesulfonic, (D, L)-tartaric, citric, maleic, (D, L)-malic, fumaric, succinic, succinate, lactate, trifluoromethanesulfonic, naphthalene-1 -sulfonic, mandelic, pyruvic, stearic, ascorbic, salicylic, and the like. When the compounds of the present application contain an acidic group, their pharmaceutically acceptable salts can also include alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as zinc, calcium or magnesium salts; organic base salts, such as those formed with ammonia, alkyl amines, including but not limited to methylamine, triethylamine, hydroxyalkyl amines, amino acids, including but not limited to lysine, arginine, N-methylglucosamine, and the like.

[0455] The term "tautomer" as used herein refers to isomers of a molecule in which a single atom moves rapidly between two positions to produce functional group isomers, such as keto and enol tautomers.

[0456] The term "isotopically enriched" as used herein refers to a compound in which one or more atoms are present in an amount greater than their natural abundance. For example, an amount of deuterium greater than its natural abundance of about 0.015%.

[0457] The term "solvate" as used herein refers to a compound of the present application in combination with a stoichiometric or non-stoichiometric amount of solvent. The solvent molecules can be present in ordered or disordered arrangements. The solvent includes, but is not limited to, water, methanol, ethanol, and the like.

[0458] The term "metabolite" as used herein refers to a substance produced by the metabolic activities of microorganisms.

[0459] The term "prodrug" means a chemical derivative of a compound of the present application which, upon in vivo chemical conversion, is converted into the compound of Formula I.

[0460] The term "crystal form" means that the ions or molecules therein are arranged in a strict periodicity in three dimensions and have a regular repeating distance. Different periodic arrangements can result in different crystal forms, i.e., polymorphism. The term "amorphous" means that the ions or molecules therein are arranged in a random manner, i.e., without a regular repeating distance.

[0461] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0462] The term "alkyl" means a straight or branched chain alkyl group having the number of carbon atoms specified. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

[0463] The term "alkoxy" means the group -O-RX, wherein Rx is alkyl as defined above.

[0464] The term "alkenyl" means a straight or branched chain unsaturated non-aromatic hydrocarbon group or cyclic alkenyl group having one or more carbon-carbon double bonds, preferably C2-C6 alkenyl. Examples of alkenyl groups include cyclopropene, cyclobutene, cyclopentene, cyclohexene and the like.

[0465] The term "alkynyl" means a straight or branched chain unsaturated non-aromatic hydrocarbon group having one or more carbon-carbon triple bonds, preferably C2-C6 alkynyl, such as ethynyl, propynyl and the like.

[0466] The term "amino" means NH2.

[0467] The term "carboxyl" means COOH.

[0468] The term "cycloalkyl" means a straight or branched chain saturated alkyl group having the number of carbon atoms specified. It can be monocyclic, bicyclic or polycyclic. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0469] The term "heterocycloalkyl" refers to a saturated monocyclic group having heteroatoms, preferably a 3-10 membered saturated monocyclic ring containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S, preferably a 3-7 membered saturated monocyclic ring, more preferably a 5-6 membered saturated monocyclic ring. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and the like. Preferred heterocyclyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl.

[0470] In the present application, the group of "heterocycle" after losing one hydrogen atom is a heterocycloalkyl group. Thus, the ring obtained after the heterocycloalkyl group of the present application obtains one hydrogen atom is a heterocycle of the present application. Similarly, the ring obtained after the aryl, heteroaryl, cycloalkyl group of the present application obtains one hydrogen atom is an aryl ring, heteroaryl ring, cycloalkane of the present application.

[0471] In the present application, C3-C6 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0472] The term "aryl" refers to phenyl or naphthyl.

[0473] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably an aromatic 5-6 membered monocyclic ring or 9-10 membered bicyclic ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, for example furanyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl and the like.

[0474] In the present application, the ligand of E3 ligase can be a group after losing one atom or atom group from the compound of formula A;

[0475]

[0476] In the compound of formula A, Q 1 , Q 3 , M 1 , M 2 and M 3 are independently C(R q1 )(R q2 ), N(R q3 ), O or S, Q 2 is C(R q4 ) or N; R q1 , Rq2 , R q3 , and R q4 are independently H, deuterium, halogen, CN, NO2, OH, oxo (=0), NH2, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0477] R 1 ' and R 2 ' are independently H, D, halogen (e.g., F, Cl, Br, or I), CN, OH, NO2, (CR m1 R m2 ) q1 COOR m3 , oxo (=0), C1-C 10 alkyl, R m4 substituted C1-C 10 alkyl, C1-C6 alkoxy, R m6 substituted C1-C6 alkoxy, -OR m7 , NH2, O(CH2) q2 (CH2) q3 NH2, (CH2) q4 (NR m5 )(CH2) q5 NH2, (CR m8 R m9 ) q7 NH2, -S-C1-C6 alkyl, -COR m10 , C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 3-10 membered heterocycloalkyl where the heteroatoms are selected from one or more of N, O, and S, the number of heteroatoms ranging from 1 to 3, C6-C 15 aryl, 5-15 membered heteroaryl where the heteroatoms are selected from one or more of N, O, and S, the number of heteroatoms ranging from 1, 2, 3, or 4, (CH2) q9 SO2R m11 , (CH2) q10 NR m5 SO2C1-C6 alkyl, -NR m5 SO2C1-C6 alkyl, -NR m5 COC1-C6 alkyl, -NR m5 (CH2) q11 CONR m5 C1-C6 alkyl, (CH2) q12 NR m5 (CH2) q13 (NR m5 ) q14 SO2R m12 , -(CR m5 Rm13 ) q15 COOR m14 , (CH2) q16 CONR m15 R m16 ;

[0478] R m1 , R m2 , R m5 , R m13 and R m14 are independently H, deuterium, C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl;

[0479] R m3 is H or C1-C6alkyl;

[0480] R m4 is halogen, OH, CN, C1-C6alkyl, C1-C6alkoxy, NH2, NR m5 C1-C6alkyl, C6-C 15 aryl, 5-15 membered heteroaryl wherein one or more heteroatoms are selected from the group consisting of N, O and S and the number of heteroatoms is 1, 2, 3 or 4, 3-10 membered heterocycloalkyl wherein one or more heteroatoms are selected from the group consisting of N, O and S and the number of heteroatoms is 1-3;

[0481] R m6 is halogen, OH, CN, C1-C6alkyl, C1-C6alkoxy, NH2, C6-C 15 aryl, 5-15 membered heteroaryl wherein one or more heteroatoms are selected from the group consisting of N, O and S and the number of heteroatoms is 1, 2, 3 or 4, or 3-10 membered heterocycloalkyl wherein one or more heteroatoms are selected from the group consisting of N, O and S and the number of heteroatoms is 1-3;

[0482] R m7 is C6-C 15 aryl, 5-15 membered heteroaryl wherein one or more heteroatoms are selected from the group consisting of N, O and S and the number of heteroatoms is 1, 2, 3 or 4, or 3-10 membered heterocycloalkyl wherein one or more heteroatoms are selected from the group consisting of N, O and S and the number of heteroatoms is 1-3;

[0483] Ring N is C3-C6cycloalkane, 3-10 membered heterocycle wherein one or more heteroatoms are selected from the group consisting of N, O and S and the number of heteroatoms is 1-3, C6-C 10 aromatic ring or 5-10 membered heteroaromatic ring wherein one or more heteroatoms are selected from the group consisting of N, O and S and the number of heteroatoms is 1-3;

[0484] R m8 and R m9independently H, OH, or CN;

[0485] R m10 C1-C6alkyl, -NH2, -NR m5 C1-C6alkyl, -NR m5 (CH2) q8 C6-C 15 aryl, -NR m5 C6-C 15 aryl, heteroatoms selected from one or more of N, O, and S, in an amount of 1, 2, 3, or 4, or 3-10 membered heterocycloalkyl, heteroatoms selected from one or more of N, O, and S, in an amount of 1-3;

[0486] R m11 -NH2, -NR m5 -C1-C6alkyl or -C1-C6alkyl;

[0487] R m15 and R m16 independently H, deuterium, C1-C6alkyl, cyano-substituted C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxyC1-C6alkyl, C3-C6cycloalkyl, C6-C 15 aryl, heteroatoms selected from one or more of N, O, and S, in an amount of 1, 2, 3, or 4, or 3-10 membered heterocycloalkyl, heteroatoms selected from one or more of N, O, and S, in an amount of 1-3; or R m15 and R m16 together with the N atom to which they are attached form a 5-15 membered heteroaryl, heteroatoms selected from one or more of N, O, and S, in an amount of 1, 2, 3, or 4, or 3-10 membered heterocycloalkyl, heteroatoms selected from one or more of N, O, and S, in an amount of 1-3;

[0488] q1, q6, q9, q10are independently 0, 1, 2, 3, 4, 5, or 6;

[0489] q2, q3, q4, q5, q7, q8, q11, q12, q13, q15, q16are independently 1, 2, 3, 4, 5, or 6;

[0490] q14is 0 or 1.

[0491] In the present application, the ligand of the E3 ligase may, for example, be a group after losing one atom or atom group from the compound of Formula A-1 to Formula A-4;

[0492]

[0493] wherein Q3 , M 1 , M 2 and M 3 independently are C(R q1 )(R q2 ), N(R q3 ), O or S, Q 2 is C(R q4 ) or N; R q1 , R q2 , R q3 and R q4 independently are H, deuterium, halogen, CN, NO2, OH, oxo (=O), NH2, carboxyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0494] R 1 ’ and R 2 ’ independently are H, D, halogen (e.g. F, Cl, Br or I), CN, OH, NO2, NH2, COOH, oxo (=O) or C1-C4 alkyl.

[0495] In the present application, the ligand of E3 ligase may, for example, be a group after losing an atom or atom group from the following compounds:

[0496]

[0497] In the present application, the ligand of E3 ligase may, for example, be any of the following groups:

[0498]

[0499] The term “ligand” is a concept in the field of biology, which refers to a molecule or group that can bind to a target protein.

[0500] The term “modulator” refers to a compound that increases or decreases the level of a target molecule or the function of a target molecule relative to a standard control (e.g. like the absence of the modulator).

[0501] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined in any manner, i.e. to obtain each preferred example of the present application.

[0502] The reagents and raw materials used in the present application are commercially available.

[0503] The positive progress effect of the present application is that the aromatic compound of the present application has a good inhibitory effect on KRAS, especially KRAS G12C. DETAILED DESCRIPTION

[0504] The application is further illustrated by the following examples without thereby limiting the application to the examples described. The experimental methods in the following examples, where no specific conditions are indicated, were carried out according to standard methods and conditions, or according to the instructions of the commercial suppliers.

[0505] Example 1: Synthesis of 4-(4-acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)quinolin-2(1H)-one

[0506]

[0507] Synthesis route:

[0508]

[0509] Step A: 2-Bromo-1-fluoro-4-iodobenzene (8.4 g, 27.92 mmol) was dissolved in anhydrous toluene (100 mL), then 2-isopropyl-6-methylaniline (5.0 g, 33.50 mmol), Pd(OAC)2 (palladium acetate, 0.627 g, 2.792 mmol), BINAP (1,1'-binaphthalene-2,2'-diphosphonic acid, 1.738 g, 2.792 mmol) and cesium carbonate (13.64 g, 41.88 mmol) were added. The reaction was refluxed under nitrogen overnight. After the starting material disappeared by liquid chromatography-mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain N-(3-bromo-4-fluorophenyl)-2-isopropyl-6-methylaniline (6.068 g, orange solid, yield 67.68%). MS (ESI) M / Z: 324.1 [M+H+].

[0510] Step B: N-(3-bromo-4-fluorophenyl)-2-isopropyl-6-methylaniline (6.068 g, 18.897 mmol) and methyl 3-chloro-3-oxopropionate (15.48 g, 113.38 mmol) were dissolved in dichloromethane (200 mL), then triethylamine (11.47 g, 113.38 mmol) was added dropwise slowly at room temperature within 2 hours and stirred for 10 minutes. After the disappearance of the starting material was monitored by LCMS, the reaction solution was diluted with dichloromethane (100 mL) and water (100 mL) was added, the mixture was extracted with dichloromethane (80 mL x 3 times), the combined organic phase was washed with saturated brine (80 mL x 3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-6-methylphenyl)amino)-3-oxopropanoate (5.3 g, yellowish solid, yield 66.6%). MS (ESI) M / Z: 424.1.1 [M+H + ].

[0511] Step C: Sodium hydroxide (5.034 g, 125.86 mmol) dissolved in 30 mL of water was added to a solution of methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-6-methylphenyl)amino)-3-oxopropanoate (5.3 g, 12.586 mmol) dissolved in methanol (120 mL) and stirred at room temperature for 1 hour. After the disappearance of the starting material was monitored by LCMS, the mixture solution was diluted with water (100 mL), then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. It was extracted twice with ethyl acetate (2 x 100 mL), the organic layer was washed with brine, dried over Na2SO4, filtered, and finally concentrated under reduced pressure. 3-((3-bromo-4-fluorophenyl)(2-isopropyl-6-methylphenyl)amino)-3-oxopropanoic acid (4.846 g, yellowish solid, yield 94.57%) was obtained. MS (ESI) M / Z: 408.0 [M+H + ].

[0512] Step D: 3-((3-bromo-4-fluorophenyl)(2-isopropyl-6-methylphenyl)amino)-3- oxopropanoic acid (4.846 g, 11.90 mmol) was dissolved in Eatons Reagent (40 mL) and stirred at 55 °C overnight. After the disappearance of the starting material was monitored by liquid mass spectrometry, the reaction was slowly added dropwise to saturated sodium bicarbonate solution and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. It was extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 7-bromo-l-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(lH,3H)-dione (4.51 g, white solid, yield 97.42%) was obtained. MS (ESI) M / Z: 392.1 [M+H + ].

[0513] Step E: 7-bromo-l-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(lH,3H)-dione (4.51 g, 11.5938 mmol) was dissolved in phosphorus oxychloride (30 mL) and stirred at 90 °C for 2 hours. After the disappearance of the starting material was monitored by liquid mass spectrometry, the phosphorus oxychloride was distilled off under reduced pressure, water (40 mL) was slowly added and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. It was extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The solid was dissolved in N,N-dimethylformamide and prepared to obtain 7-bromo-4-chloro-6-fluoro-l-(2-isopropylphenyl)quinolin-2(lH)-one (0.705 g, yellow solid, yield 14.94%). MS (ESI) M / Z: 408.1 [M+H + ].

[0514] Step F: 7-bromo-4-chloro-6-fluoro-l-(2-isopropylphenyl)quinolin-2(lH)-one (0.705 g, 1.732 mmol) was dissolved in dioxane (10 mL), then piperazine-l-carboxylate tert-butyl ester (1.613 g, 8.661 mmol) and N,N-diisopropylethylamine (2.239 g, 17.32 mmol) were added and stirred at 110 °C for 2 days. After the disappearance of the starting material was monitored by liquid mass spectrometry, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 2) to obtain 4-(7-bromo-6-fluoro-l-(2-isopropyl-6-methylphenyl)-2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylate tert-butyl ester (0.832 g, white solid, yield 86.21%). MS (ESI) M / Z: 558.1 [M+H + ].

[0515] 1H NMR (400MHz, CDCl3) δ7.58–7.51(m,1H),7.46–7.35(m,2H),7.25(s,1H),6.74–6.53(m,1H),6.32(d,J=4.7Hz,1H),3 .70(s,4H),3.13(s,4H),2.47–2.38(m,1H),1.95(s,3H),1.51(s,9H),1.15(d,J=6.8Hz,3H),1.03(d,J=6.9Hz,3H).

[0516] Step G: 4-(7-bromo-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinoline-4-yl)piperazine-1-carboxylic acid tert-butyl ester (0.400 g, 0.7179 mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.234 g, 1.4358 mmol), potassium orthophosphate (305 mg, 1.4358 mmol), and Pd2dba3 (tris(dibenzylideneacetone)palladium, 0.099 g, 0.1077 mmol) and PA- A mixture of pH (1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphorylamidoane, 0.063 g, 0.2154 mmol) was dissolved in a mixture of 1,4-dioxane and water (8 mL / 2 mL) after the air was purged with argon for 15 minutes. The mixture was then purged with argon again and stirred at 60 °C for 3 days. After the liquid chromatography-mass spectrometry showed that the starting material had disappeared, the mixture was extracted twice with ethyl acetate (2 × 40 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinoline-4-yl)piperazine-1-carboxylic acid tert-butyl ester (0.340 g, pale yellow solid, yield 80.3%).

[0517] MS(ESI)M / Z: 590.2 [M+H] + ].

[0518] Step H: 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(2-isopropyl-6- methylphenyl)-2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.200 g, 0.339 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 hour, after liquid mass spectrometry monitoring showed the disappearance of the starting material, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added again and concentrated under reduced pressure until the dichloromethane and trifluoroacetic acid were completely removed, to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(2-isopropyl-6- methylphenyl)-4-(piperazin-l-yl)quinolin-2(lH)-one (0.166 g, brown solid, yield 100%). MS (ESI) M / Z: 490.2 [M+H + ].

[0519] Step I: 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(2-isopropyl-6-methylphenyl)-4- (piperazin-l-yl)quinolin-2(lH)-one (0.166 g, 0.339 mmol) was dissolved in dichloromethane (13 mL) and DIPEA (N,N-diisopropylethylamine) (0.219 g, 1.695 mmol) and acryloyl chloride (0.031 g, 0.339 mmol) were added and stirred at room temperature for 2 hours, after LCMS monitoring showed the disappearance of the starting material, the solvent was removed by concentration under reduced pressure and the resulting solid was dissolved in N,N-dimethylformamide (5 mL) to prepare 4-(4-acryloylpiperazin-l-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(2- isopropyl-6-methylphenyl)quinolin-2(lH)-one (0.0329 g, white solid, yield 17.85%). MS (ESI) M / Z: 544.2 [M+H + ].

[0520] 1 H NMR (400 MHz, DMSO) δ 10.08 (s, 1H), 7.71 (d, J = 10.2 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.28 - 7.14 (m, 2H), 6.95 - 6.81 (m, 1H), 6.77 - 6.63 (m, 2H), 6.40 - 6.31 (m, 1H), 6.24 (s, 1H), 6.23 - 6.15 (m, 1H), 5.80 - 5.71 (m, 1H), 3.86 (s, 4H), 3.20 (s, 4H), 2.47 - 2.32 (m, 1H), 1.84 (d, J = 20.9 Hz, 3H), 1.11 - 0.88 (m, 6H).

[0521] Example 2: Synthesis of 4-(4-acryloylpiperazin-l-yl)-l-(2-ethyl-6-methylphenyl)-6- fluoro-7-(2-fluoro-6-hydroxyphenyl)quinolin-2(lH)-one

[0522]

[0523] Synthesis route:

[0524]

[0525] Step A (Step A): Put 2-bromo-l-fluoro-4-iodobenzene (5.0 g, 16.62 mmol), 2- ethyl-6-methylaniline (2.25 g, 16.62 mmol), palladium acetate (0.373 g, 1.7 mmol), BIANP (1,1'-binaphthalene-2,2'-diphenylphosphine, 1.03 g, 1.7 mmol) and cesium carbonate (8.12 g, 24.93 mmol) into a 250 mL single-neck flask, add anhydrous toluene (100 mL), replace with nitrogen for 3 times, then heat at 100 degrees for 16 hours. Cool and filter, wash the filter cake with ethyl acetate. Concentrate the filtrate, purify the obtained residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain N-(3-bromo-4-fluorophenyl)-2-ethyl-6-methylaniline (4.2 g, brown-black oily substance, yield 82%). MS (ESI) M / Z: 308 [M+H + ].

[0526] Step B (Step B): Put N-(3-bromo-4-fluorophenyl)-2-ethyl-6-methylaniline (5.0 g, 16.22 mmol) and 3-chloro-3-oxopropionic acid methyl ester (13.29 g, 97.34 mmol) into a 250 mL single-neck flask, add anhydrous dichloromethane (150 mL), cool to 0 degrees, slowly add triethylamine (16.77 g, 130 mmol). Then stir at room temperature for one hour. Add dichloromethane (200 mL) to the reaction solution, wash with water and saturated sodium chloride each once, dry the organic phase with anhydrous sodium sulfate and concentrate, purify the obtained residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to obtain 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylanilino)-3-oxopropionic acid methyl ester (4.2 g, brown oily substance, yield 63%). MS (ESI) M / Z: 409 [M+H + ].

[0527] Step C: Methyl 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)- 3-oxopropanoate (5.0 g, 12.25 mmol) and sodium hydroxide (2.45 g, 61.23 mmol) were placed in a 250 mL single-necked flask, and tetrahydrofuran (100 mL) and water (20 mL) were added. Stirring was performed at room temperature for 16 hours. Most of the tetrahydrofuran was distilled off, 100 mL of water was added, and the pH was adjusted to 3 with 1 mol / L hydrochloric acid. Extraction was performed with ethyl acetate (100 mL x 3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3- oxopropanoic acid (4.2 g, yellow solid, yield: 87%). MS (ESI) M / Z: 394 [M+H + ].

[0528] Step D: 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3- oxopropanoic acid (4.2 g, 10.65 mmol) and Eaton's reagent (15 mL) were placed in a 100 mL single-necked flask, and heating was performed at 90 degrees for 16 hours. Cooling was performed, the pH was adjusted to 9 with saturated potassium carbonate solution, extraction was performed with ethyl acetate (100 mL x 3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give 7-bromo-1-(2-ethyl-6-methylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (3.5 g, yellow solid, yield 87%). MS (ESI) M / Z: 377 [M+H + ].

[0529] Step E: 7-bromo-1-(2-ethyl-6-methylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione was placed in a 100 mL single-necked flask, 20 mL of phosphorus oxychloride was added, and heating was performed at 80 degrees for 3 hours. Cooling was performed, most of the phosphorus oxychloride was distilled off, the pH was adjusted to 9 with saturated potassium carbonate solution, extraction was performed with ethyl acetate (100 mL x 3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 7-bromo-4-chloro-1-(2-ethyl-6-methylphenyl)-6-fluoroquinolin-2(1H)-one (1.0 g, yellowish solid, yield 30%). MS (ESI) M / Z: 395 [M+H + ].

[0530] Step F: 7-Bromo-4-chloro-l-(2-ethyl-6-methylphenyl)-6-fluoroquinolin-2(lH)-one (1.0 g, 2.53 mmol), piperazine-l-carboxylic acid tert-butyl ester (2.36 g, 12.7 mmol) and DIPEA (N,N-diisopropylethylamine, 1.36 g, 12.7 mmol) were placed in a 50 mL single necked flask, 5 mL of 1,4-dioxane was added, then heated to 110 °C for 3 days. The reaction was monitored by LC-MS and when the starting material was consumed, the reaction was directly concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 5) to give 4-(7-bromo-l-(2-ethyl-6-methylphenyl)-6-fluoro-2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.8 g, yellowish solid, yield 58%). MS (ESI) M / Z: 544 [M+H + ].

[0531] Step G: 4-(7-Bromo-l-(2-ethyl-6-methylphenyl)-6-fluoro-2-oxo-l,2-dihydroquinolin-4- yl)piperazine-l-carboxylic acid tert-butyl ester (0.4 g, 0.73 mmol), 2-fluoro-6-hydroxybenzeneboronic acid (0.229 g, 1.47 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6- phosphorinan (44 mg, 0.14 mmol), potassium phosphate (312 mg, 1.47 mmol) and Pd2dba3 (tris(dibenzylideneacetone)dipalladium, 67 mg, 0.07 mmol) were placed in a 50 mL single necked flask, solvent tetrahydrofuran (10 mL) and water (2.5 mL) were added, purged with nitrogen three times, heated to 60 °C for 16 hours. Cooled to room temperature, ethyl acetate (100 mL) was added, washed with saturated sodium chloride (20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 5) to give 4-(l-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-l,2- dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.2 g, yellowish solid, yield 38%). MS (ESI) M / Z: 576 [M+H+].

[0532] Step H: 4-(1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2- oxo-1,2-dihydroquinolin-4-yl)piperazine-1 -carboxylic acid tert-butyl ester (0.2 g, 0.28 mmol) was dissolved in 5 mL of dichloromethane, trifluoroacetic acid (0.272 g, 2.8 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS and the starting material was consumed. The reaction was concentrated directly and dried by azeotroping with dichloromethane twice to give the product 1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazin-1-yl)quinolin-2(1 H)-one 2,2,2-trifluoroacetate salt (0.2 g, light yellow solid, 92% yield). MS (ESI) M / Z: 476 [M+H] + .

[0533] Step I: 1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazin-1- yl)quinolin-2(1 H)-one 2,2,2-trifluoroacetate salt (0.2 g, 73% purity, 0.255 mmol) and triethylamine (77 mg, 0.75 mmol) were dissolved in 5 mL of dichloromethane and cooled to 0 °C. Allyl chloride (23 mg, 0.255 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated directly and purified by preparative HPLC to give 4-(4-acryloylpiperazin-1-yl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)quinolin-2(1 H)-one (23 mg, white solid, 23% yield). MS (ESI) M / Z: 530 [M+H + ].

[0534] 1H NMR (400 MHz, DMSO) δ 10.10 (d, J = 12.8 Hz, 1H), 7.70 (d, J = 10.2 Hz, 1H), 7.41 - 7.14 (m, 4H), 6.93 - 6.81 (m, 1H), 6.78 - 6.63 (m, 2H), 6.37 (d, J = 2.9 Hz, 1H), 6.27 - 6.09 (m, 2H), 5.82 - 5.69 (m, 1H), 3.86 (s, 4H), 3.19 (s, 4H), 2.25 - 2.10 (m, 2H), 1.86 (d, J = 17.4 Hz, 3H), 1.05 - 0.89 (m, 3H).

[0535] Example 3: Synthesis of 4-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2- fluoro-6-hydroxyphenyl)quinolin-2(1 H)-one

[0536]

[0537] Synthesis route:

[0538]

[0539] Step A: 2-Bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) was dissolved in anhydrous toluene (100 mL), then 2,6-dimethylaniline (4.83 g, 39.88 mmol), Pd(OAC)2 (palladium acetate 0.746 g, 3.323 mmol), BINAP (1,1'-binaphthalene-2,2'-diphosphonic acid, 2.069 g, 3.323 mmol) and Cs2CO3 (cesium carbonate, 16.24 g, 49.8 mmol) were added. The reaction was refluxed under nitrogen overnight. After the starting material was consumed by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, orange oil, yield 93.4%).

[0540] MS (ESI) M / Z: 296.0 [M+H] + .

[0541] Step B: N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, 31.06 mmol) and methyl 3-chloro-3-oxopropionate (25.44 g, 186.35 mmol) were dissolved in dichloromethane (300 mL), then triethylamine (18.86 g, 186.35 mmol) was slowly added dropwise at room temperature over 3 hours and stirred for 10 minutes. After the starting material was consumed by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with dichloromethane (200 mL) and water (2 x 200 mL) was added, the mixture was extracted with dichloromethane (100 mL x 3 times), the organic phase was washed with saturated brine (80 mL x 3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-oxopropionate (8.8 g, yellow oil, yield 72%). MS (ESI) M / Z: 396.1 [M+H] + .

[0542] Step C: To a solution of 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)- 3-oxopropanoic acid methyl ester (8.8 g, 22.39 mmol) dissolved in methanol (240 mL) was added a solution of sodium hydroxide (8.957 g, 223.9 mmol) dissolved in 60 mL of water and stirred at room temperature for 1 h. After the disappearance of the starting material was monitored by LC-MS, the mixture solution was diluted with water (200 mL) and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. It was extracted twice with ethyl acetate (2 x 200 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 3-((3-Bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3- oxopropanoic acid (7.7 g, colorless oil, 90.7% yield) was obtained. MS (ESI) M / Z: 380.0 [M+H + ].

[0543] Step D: 3-((3-Bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-oxopropanoic acid (6.7 g, 17.67 mmol) was dissolved in Eatons Reagent (40 mL) and stirred at 55 °C overnight. After the disappearance of the starting material was monitored by LC-MS, the reaction solution was added dropwise slowly into saturated sodium bicarbonate solution and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. It was extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude 7-bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione, (mixture, 6.25 g, white solid, 97% yield) was obtained. MS (ESI) M / Z: 362.0 [M+H + ].

[0544] Step E: 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (6.25 g, 17.31 mmol) was dissolved in phosphorus oxychloride (40 mL) and stirred at 90 °C for 2 h. After the disappearance of the starting material was monitored by LC-MS, the phosphorus oxychloride was removed by distillation under reduced pressure, water (20 mL) was added slowly and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. It was extracted twice with ethyl acetate (2 x 50 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 7-bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline-2(1H)-dione (1.02 g, white solid, 15.5% yield). MS (ESI) M / Z: 296.0 [M+H] + .

[0545] Step F: 7-Bromo-4-chloro-l-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline- 2(lH)-dione (0.65 g, 1.71 mmol) was dissolved in dioxane (4.5 mL), then tert- butyl piperazine-l-carboxylate (1.59 g, 8.55 mmol) and N,N-diisopropylethylamine (2.21 g, 17.1 mmol) were added and stirred at 110 °C for 2 days. After LCMS monitoring showed the starting material was consumed, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 2) to give tert-butyl 4-(7-bromo-l-(2,6-dimethylphenyl)-6-fluoro-2-oxo-l,2- dihydroquinoline-4-yl)piperazine-l-carboxylate (0.711 g, white solid, yield 78.6%).

[0546] MS (ESI) M / Z: 530.2 [M+H + ].

[0547] Step G: A mixture of tert-butyl 4-(7-bromo-l-(2,6-dimethylphenyl)-6-fluoro-2- oxo-l,2-dihydroquinoline-4-yl)piperazine-l-carboxylate (0.711 g, 1.34 mmol), 2- fluoro-6-hydroxybenzeneboronic acid (0.419 g, 2.688 mmol), potassium phosphate tribasic (570 mg, 2.688 mmol) and Pd2dba3(tri(2-benzylidene-1- propyl-1H-imidazol-3-ium-3-yl)borate, 0.184 g, 0.21 mmol) and PA-PH (1,3,5,7- tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphorinane, 0.177 g, 0.4 mmol) was dissolved in a mixture of 1,4-dioxane and water (15 mL, 4 / 1) which was replaced with argon for 15 minutes, replaced with argon again, and stirred at 60 °C for 3 days. After LCMS monitoring showed the starting material was consumed, it was extracted with ethyl acetate (2 x 40 mL) twice, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by preparative purification to give tert-butyl 4-(l-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-2-oxo-l,2-dihydroquinoline-4-yl)piperazine-l-carboxylate (0.251 g, yellowish solid, yield 33.2%).

[0548] MS (ESI) M / Z: 562.2 [M+H] + .

[0549] Step H: 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo- 1,2-dihydroquinolin-4-yl)piperazine-1 -carboxylic acid tert-butyl ester (0.251 g, 0.447 mmol) was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (4.2 mL) was added and stirred at room temperature for 1 h, after the disappearance of the starting material was monitored by LC-MS, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure and dichloromethane (10 mL) was added and again concentrated under reduced pressure until the dichloromethane and trifluoroacetic acid were completely removed to give 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-4-(piperazin-1-yl)quinolin-2(1 H)-one (0.206 g, brown solid, 96.8% yield).

[0550] MS (ESI) M / Z: 462.3 [M+H+].

[0551] Step I: 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazin-1- yl)quinolin-2(1 H)-one (0.206 g, 0.447 mmol) was dissolved in dichloromethane (9 mL) and DIEA (N,N-diisopropylethylamine) (0.289 g, 2.235 mmol) and acryloyl chloride (0.041 g, 0.447 mmol) were added and stirred at room temperature for 2 h, after the disappearance of the starting material was monitored by LC-MS, the solvent was removed by concentration under reduced pressure and the resulting solid was dissolved in N,N-dimethylformamide (5 mL) to give 4-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)quinolin-2(1 H)-one (0.1276 g, white solid, 55.4% yield) which was used for the next step without further purification.

[0552] MS (ESI) M / Z: 516.2 [M+H+].

[0553] 1H NMR (400 MHz, DMSO) d 10.12 (s, 1H), 7.71 (d, J = 10.3 Hz, 1H), 7.36 - 7.15 (m, 4H), 6.94 - 6.81 (m, 1H), 6.76 - 6.65 (m, 2H), 6.38 (d, J = 6.2 Hz, 1H), 6.26 - 6.09 (m, 2H), 5.79 - 5.69 (m, 1H), 3.86 (s, 4H), 3.19 (s, 4H), 1.88 (d, J = 15.5 Hz, 6H).

[0554] Example 4: Synthesis of 4-(4-acryloylpiperazin-l-yl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-l-(2-isopropyl-4-methylpyridin-3-yl)quinolin-2(lH)-one

[0555]

[0556] Synthesis route:

[0557]

[0558] Step A (Step A): Put 2-bromo-l-fluoro-4-iodobenzene (10.0 g, 33.23 mmol), 2- isopropyl-4-methyl-3-aminopyridine (4.99 g, 33.23 mmol), palladium acetate (0.746 g, 3.32 mmol), BIANP (1,1'-binaphthalene-2,2'-diphenylphosphine, 2.07 g, 3.32 mmol) and cesium carbonate (16.24 g, 49.85 mmol) into a 500 mL single-neck flask, add anhydrous toluene (200 mL), replace with nitrogen for 3 times, then heat at 100 degrees for 16 hours. Cool and filter, wash the filter cake with ethyl acetate. Concentrate the filtrate, and purify the residue obtained by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methyl-3- aminopyridine (7.9 g, brown oil, yield 74%).

[0559] MS (ESI) M / Z: 323 [M+H + ].

[0560] Step B (Step B): Put N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methyl-3- aminopyridine (7.9 g, 24.44 mmol) and methyl 3-chloro-3-oxopropionate (10.01 g, 73.33 mmol) into a 250 mL single-neck flask, add anhydrous dichloromethane (150 mL), cool to 0 degrees, and slowly add triethylamine (12.3 g, 122 mmol). Then stir at room temperature for one hour. Add dichloromethane (200 mL) to the reaction solution, wash with water and saturated sodium chloride each once, dry the organic phase with anhydrous sodium sulfate and concentrate, and purify the residue obtained by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3- oxopropionate (3.5 g, brown oil, yield 34%). MS (ESI) M / Z: 423 [M+H+].

[0561] Step C: Methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3- yl)amino)-3-oxopropanoate (3.5 g, 8.27 mmol) and sodium hydroxide (1.65 g, 41.34 mmol) were placed in a 250 mL single necked flask, tetrahydrofuran (100 mL) and water (20 mL) were added. Stirring was carried out at room temperature for 16 hours. Most of the tetrahydrofuran was evaporated, 100 mL of water was added, pH was adjusted to 7 with 1 M hydrochloric acid. Extraction was carried out with dichloromethane (100 mL x 3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3- oxopropanoic acid (3.2 g, yellow solid, yield: 95%). MS (ESI) M / Z: 409 [M+H] + .

[0562] Step D: 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3- oxopropanoic acid (3.2 g, 7.82 mmol) and Eaton’s reagent (15 mL) were placed in a 100 mL single necked flask, then heated to 90 degrees for 16 hours. Cooling was carried out, pH was adjusted to 9 with saturated potassium carbonate solution, extraction was carried out with dichloromethane (100 mL x 3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated to give 7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinoline- 2,4(1H,3H)-dione (2.6 g, yellow solid, yield 85%). MS (ESI) M / Z: 391 [M+H] + .

[0563] Step E: 7-bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinoline-2,4(1H,3H)- dione (2.6 g, 6.65 mmol) was placed in a 100 mL single necked flask, 20 mL of phosphorus oxychloride was added, then heated to 80 degrees for 3 hours. Cooling was carried out, most of the phosphorus oxychloride was evaporated, pH was adjusted to 9 with saturated potassium carbonate solution, extraction was carried out with dichloromethane (100 mL x 3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the crude product was concentrated, purified by high performance liquid preparation to give 7-bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinolin- 2(1H)-one (0.4 g, white solid, yield 15%). MS (ESI) M / Z: 409 [M+H] + .

[0564] Step F: 7-Bromo-4-chloro-6-fluoro-l-(2-isopropyl-4-methylpyridin-3-yl)quinolin- 2(lH)-one (0.4 g, 0.98 mmol), piperazine-l-carboxylic acid tert-butyl ester (909 mg, 4.88 mmol) and DIPEA (N,N-diisopropylethylamine, 631 mg, 4.88 mmol) were put together in a 50 mL single neck flask, 3 mL of 1,4-dioxane was added, then heated to 110 °C for 3 days. The reaction was monitored by LC-MS and the starting material was consumed. The reaction mixture was directly concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 9) to give 4-(7-bromo-6-fluoro-l-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-l,2- dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.35 g, yellowish solid, 64% yield). MS (ESI) M / Z: 559 [M+H] + .

[0565] Step G: A mixture of 4-(7-bromo-6-fluoro-l-(2-isopropyl-4-methylpyridin-3-yl)-2- oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.35 g, 0.63 mmol), 2-fluoro-6-hydroxybenzeneboronic acid (0.195 g, 1.26 mmol), potassium phosphate (267 mg, 1.26 mmol) and Pd2dba3 (tris(dibenzylideneacetone)dipalladium, 0.027 g, 0.03 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphanorbornane, 0.030 g, 0.06 mmol) were dissolved in a mixture of 1,4-dioxane and water (10 mL, 4 / 1) which was purged with argon for 15 minutes, purged again with argon and stirred at 60 °C overnight. After the starting material was consumed as monitored by LC-MS, the reaction mixture was extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The crude product was purified by preparative purification to give 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(2-isopropyl-4- methylpyridin-3-yl)-2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.25 g, yellowish solid, 68% yield). MS (ESI) M / Z: 591 [M+H] + .

[0566] Step H: 4-(6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(2-isopropyl-4- methylpyridin-3-yl)-2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.25 g, 0.423 mmol) was dissolved in 5 mL of dichloromethane, trifluoroacetic acid (0.482 g, 4.23 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and the starting material was consumed. The reaction was concentrated directly and dried by azeotroping with dichloromethane twice to give the product 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(2-isopropyl-4- methylpyridin-3-yl)-4-(piperazin-l-yl)quinolin-2(lH)-one 2,2,2-trifluoroacetate salt, 0.24 g, light yellow solid, 97% yield. MS (ESI) M / Z: 491 [M+H] + .

[0567] Step I: 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-l-(2-isopropyl-4-methylpyridin-3- yl)-4-(piperazin-l-yl)quinolin-2(lH)-one 2,2,2-trifluoroacetate salt (0.25 g, 0.4 mmol) and triethylamine (80 mg, 0.8 mmol) were dissolved in 5 mL of dichloromethane, cooled to 0 degree, acryloyl chloride (36 mg, 0.4 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated directly and purified by preparative HPLC to give 4-(4-acryloylpiperazin-l-yl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-l-(2-isopropyl-4-methylpyridin-3-yl)quinolin-2(lH)-one (60 mg, white solid, 68% yield). MS (ESI) M / Z: 545 [M+H] + .

[0568] 1 H NMR (400 MHz, CDC13) δ 10.27 (s, 1H), 8.38 (s, 1H), 7.64 (d, J = 10.0 Hz, 1H), 7.23 - 7.08 (m, 2H), 6.80 - 6.58 (m, 4H), 6.43 - 6.34 (m, 1H), 6.31 (s, 1H), 5.86 - 5.73 (m, 1H), 3.95 (d, J = 44.9 Hz, 4H), 3.27 (d, J = 17.0 Hz, 4H), 2.71 (d, J = 6.8 Hz, 1H), 1.16 (d, J = 6.7 Hz, 3H), 0.99 (s, 3H).

[0569] Example 5: Synthesis of 4-(4-acryloylpiperazin-l-yl)-7-(2-amino-6-chlorophenyl)-l-(2- ethyl-6-methylphenyl)-6-fluoroquinolin-2(lH)-one

[0570]

[0571] Synthesis route:

[0572]

[0573] Step A: 4-(7-bromo-l-(2-ethyl-6-methylphenyl)-6-fluoro-2-oxo-l,2-dihydroquinolin-4- yl)piperazine-l-carboxylate (0.3 g, 0.55 mmol), (2-amino-6-chlorophenyl)boronic acid (0.142 g, 0.83 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphanorbornane (32 mg, 0.11 mmol), potassium phosphate (233 mg, 1.1 mmol) and Pd2dba3 (55 mg, 0.06 mmol) were put into a 50 mL single necked flask, solvent tetrahydrofuran (8 mL) and water (2 mL) were added, purged with nitrogen for three times, heated to 60 degree for 16 hours. Cool down to room temperature, add ethyl acetate (100 mL) and wash with saturated sodium chloride (20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 5) to give 4-(7-(2-amino-6-chlorophenyl)-l-(2-ethyl-6-methylphenyl)-6-fluoro-2-oxo-l,2- dihydroquinolin-4-yl)piperazine-l-carboxylate (30 mg, yellowish solid, yield 9%).

[0574] MS (ESI) M / Z: 591 [M+H] + .

[0575] Step B: 4-(7-(2-amino-6-chlorophenyl)-l-(2-ethyl-6-methylphenyl)-6-fluoro-2-oxo-l,2- dihydroquinolin-4-yl)piperazine-l-carboxylate (30 mg, 0.06 mmol) was dissolved in 2 mL of dichloromethane, trifluoroacetic acid (63 mg, 0.6 mmol) was added. Reaction at room temperature for 2 hours, LCMS showed the starting material was consumed, directly concentrate, take with dichloromethane for 2 times to give the product 7-(2-amino-6-chlorophenyl)-l-(2-ethyl-6-methylphenyl)-6-fluoro-4-(piperazin-l- yl)quinolin-2(lH)-one 2,2,2-trifluoroacetate (33 mg, yellowish solid, yield 99%). + .

[0576] Step C: 7-(2-amino-6-chlorophenyl)-l-(2-ethyl-6-methylphenyl)-6-fluoro-4- (piperazin-l-yl)quinolin-2(lH)-one 2,2,2-trifluoroacetate (33 mg, 0.061 mmol) and triethylamine (12 mg, 1.2 mmol) were dissolved in 2 mL of dichloromethane, cooled to 0 degrees, and allyl chloride (5.5 mg, 0.061 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was directly concentrated and the product was prepared by high performance liquid chromatography to give two products, 4-(4-allylpiperazin-l-yl)-7-(2-amino-6-chlorophenyl)-l-(2-ethyl-6- methylphenyl)-6-fluoroquinolin-2(lH)-one, 3.5 mg, white solid, 10.5% yield and 4-(4- allylpiperazin-l-yl)-7-(2-amino-6-chlorophenyl)-l-(2-ethyl-6-methylphenyl)-6-fluoroquinolin- 2(lH)-one (2.5 mg, white solid, 7.5% yield). MS (ESI) M / Z: 545 [M+H] + .

[0577] First product 1-al NMR: 1 H NMR (400 MHz, CDC13) δ 7.65 (d, J = 9.7 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.70 - 6.59 (m, 2H), 6.50 (d, J = 6.1 Hz, 1H), 6.41 - 6.32 (m, 2H), 5.84 - 5.73 (m, 1H), 3.96 (d, J = 56.0 Hz, 4H), 3.52 (s, 2H), 3.25 (s, 4H), 2.42 - 2.17 (m, 2H), 1.97 (s, 3H), 1.06 (t, J = 7.6 Hz, 3H).

[0578] Second product 1-a2 NMR: 1H NMR (400 MHz, CDC13) δ 7.65 (d, J = 9.7 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J = 7.4 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.70 - 6.59 (m, 2H), 6.50 (d, J = 6.1 Hz, 1H), 6.43 - 6.34 (m, 2H), 5.83 - 5.76 (m, 1H), 3.96 (d, J = 63.1 Hz, 4H), 3.53 (s, 2H), 3.25 (s, 4H), 2.40 - 2.18 (m, 2H), 1.98 (s, 3H), 1.07 (t, J = 7.6 Hz, 3H).

[0579] Example 6: Synthesis of 4-(4-acryloylpiperazin-l-yl)-l-(2,6-diethylphenyl)-6- fluoro-7-(2-fluorophenyl)quinolin-2(lH)-one

[0580]

[0581] Synthesis route:

[0582]

[0583] The synthesis steps are the same as Example 4.

[0584] MS (ESI) M / Z: 528.3 [M+H] +

[0585] 1H NMR (500 MHz, CDC13) δ 7.59 (d, J = 10.3 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.36 (d, J = 6.4 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.18 (dt, J = 14.6, 7.4 Hz, 2H), 7.11 (t, J = 9.1 Hz, 1H), 6.65 (dd, J = 16.7, 10.6 Hz, 1H), 6.56 (d, J = 6.1 Hz, 1H), 6.39 (t, J = 8.0 Hz, 2H), 5.80 (d, J = 10.5 Hz, 1H), 3.94 (d, J = 62.8 Hz, 4H), 3.25 (s, 4H), 2.34 (dt, J = 14.9, 7.4 Hz, 2H), 2.23 (dd, J = 15.0, 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 6H).

[0586] Example 7: 4-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4- methoxyphenyl)quinolin-2(1H)-one

[0587]

[0588] Synthetic route:

[0589]

[0590] Step A: 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) was dissolved in anhydrous toluene (100 mL), then 2,6-dimethylaniline (4.83 g, 39.88 mmol), Pd(OAC)2 (palladium acetate 0.746 g, 3.323 mmol), BINAP (1,1'-binaphthalene-2,2'-diphenylphosphine, 2.069 g, 3.323 mmol) and Cs2CO3 (cesium carbonate, 16.24 g, 49.8 mmol) were added. The reaction was refluxed under nitrogen overnight. After the starting material was consumed by LC-MS, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, orange oil, yield 93.4%). MS (ESI) M / Z: 296.0 [M+H] + .

[0591] Step B: N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, 31.06 mmol) and methyl 3-chloro-3-oxopropionate (25.44 g, 186.35 mmol) were dissolved in dichloromethane (300 mL), then triethylamine (18.86 g, 186.35 mmol) was added dropwise slowly at room temperature for 3 hours and stirred for 10 minutes. After the starting material was consumed by LC-MS, the reaction solution was diluted with dichloromethane (200 mL) and water (2 x 200 mL) was added, the mixture was extracted with dichloromethane (100 mL x 3 times), the organic phase was combined, first washed with saturated brine (80 mL x 3 times), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give methyl 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-oxopropionate (8.8 g, yellow oil, yield 72%). MS (ESI) M / Z: 396.1 [M+H] + .

[0592] Step C: To a solution of 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)- 3-oxopropanoic acid methyl ester (8.8 g, 22.39 mmol) dissolved in methanol (240 mL) was added a solution of sodium hydroxide (8.957 g, 223.9 mmol) dissolved in 60 mL of water and stirred at room temperature for 1 h. After the disappearance of the starting material was monitored by LC-MS, the mixture solution was diluted with water (200 mL) and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. It was extracted twice with ethyl acetate (2 x 200 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 3-((3-Bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3- oxopropanoic acid (7.7 g, colorless oil, 90.7% yield) was obtained. MS (ESI) M / Z: 380.0 [M+H] + .

[0593] Step D: 3-((3-Bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-oxopropanoic acid (6.7 g, 17.67 mmol) was dissolved in Eatons Reagent (40 mL) and stirred at 55 °C overnight. After the disappearance of the starting material was monitored by LC-MS, the reaction solution was added dropwise slowly into saturated sodium bicarbonate solution and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. It was extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude 7-bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline- 2,4(1H,3H)-dione, (mixture, 6.25 g, white solid, 97% yield) was obtained. MS (ESI) M / Z: 362.0 [M+H] + .

[0594] Step E: 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (6.25 g, 17.31 mmol) was dissolved in phosphorus oxychloride (40 mL) and stirred at 90 °C for 2 h. After the disappearance of the starting material was monitored by LC-MS, the phosphorus oxychloride was removed by distillation under reduced pressure, water (20 mL) was added slowly and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. It was extracted twice with ethyl acetate (2 x 50 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 7-bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline- 2(1H)-dione (1.02 g, white solid, 15.5% yield). MS (ESI) M / Z: 296.0 [M+H] + .

[0595] Step F: 7-Bromo-4-chloro-l-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline- 2(lH)-dione (300 mg, 0.78 mmol) was dissolved in dioxane (4.5 mL), then tert-butyl piperazine-l-carboxylate (725 mg, 3.9 mmol) and N,N- diisopropylethylamine (603.0 mg, 4.68 mmol) were added and stirred at 110 °C for 2 days. After LCMS monitoring showed the disappearance of the starting material, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 2) to give tert-butyl 4-(7-bromo-l-(2,6-dimethylphenyl)-6-fluoro-2-oxo-l,2- dihydroquinoline-4-yl)piperazine-l-carboxylate (205 mg, white solid, yield 50%). MS (ESI) M / Z: 530.2 [M+H] + .

[0596] Step G: tert-Butyl 4-(7-bromo-l-(2,6-dimethylphenyl)-6-fluoro-2-oxo-l,2- dihydroquinoline-4-yl)piperazine-l-carboxylate (60 mg, 0.11 mmol), 2-fluoro-4- methoxybenzenboronic acid (96 mg, 0.56 mmol), potassium acetate (89 mg, 0.91 mmol) and PdCl2(pddf) (8 mg, 0.01 mmol) were dissolved in a mixture of 1,4- dioxane and water (1 mL, 4 / 1) which was replaced with argon for 15 minutes, replaced with argon again, and stirred at 60 °C for 3 days. After LCMS monitoring showed the disappearance of the starting material, it was extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by preparative purification to give tert-butyl 4-(l-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4- methoxyphenyl)-2-oxo-l,2-dihydroquinoline-4-yl)piperazine-l-carboxylate (60 mg, yellowish solid, yield 94.8%). MS (ESI) M / Z: 576.2 [M+H] + .

[0597] Step H: 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-oxo- 1,2-dihydroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 hour, after liquid chromatography-mass spectrometry monitoring showed the starting material was consumed, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and again concentrated under reduced pressure until the dichloromethane and trifluoroacetic acid were completely removed to give 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4- (piperazin-1-yl)quinolin-2(1H)-one (40 mg, brown solid, yield 76.5%). MS (ESI) M / Z: 476.2 [M+H] + .

[0598] Step I: 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4- (piperazin-1-yl)quinolin-2(1H)-one (40 mg, 0.084 mmol) was dissolved in dichloromethane (1 mL) and DIPEA (N,N-diisopropylethylamine) (21.67 g, 0.168 mmol) and acryloyl chloride (15 mg, 0.168 mmol) were added and stirred at room temperature for 2 hours, after liquid chromatography-mass spectrometry monitoring showed the starting material was consumed, the solvent was removed by concentration under reduced pressure and the resulting solid was dissolved in N,N-dimethylformamide (5 mL) to prepare purification to give 4-(4-acryloylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6- hydroxyphenyl)quinolin-2(1H)-one (30.4 mg, white solid, yield 68.4%). MS (ESI) M / Z: 530.2 [M+H] +

[0599] 1 H NMR (500 MHz, DMSO) δ 7.74 (d, J = 10.5 Hz, 1H), 7.33 - 7.30 (m, 1H), 7.28 (d, J = 7.0 Hz, 2H), 7.21 (t, J = 8.5 Hz, 1H), 6.96 - 6.84 (m, 3H), 6.34 (d, J = 6.5 Hz, 1H), 6.23 (d, J = 8.5 Hz, 1H), 6.18 (dd, J = 16.5, 2.4 Hz, 1H), 5.75 (dd, J = 10.5, 2.5 Hz, 1H), 3.86 (d, J = 13.0 Hz, 4H), 3.77 (d, J = 10.0 Hz, 3H), 3.19 (s, 4H), 1.88 (d, J = 9.5 Hz, 6H).

[0600] Example 8: Synthesis of 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4- methoxyphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)-N-(2-methoxyethyl)piperazine-1- carboxamide

[0601]

[0602] Synthesis route:

[0603]

[0604] Step A: 2-Methoxyethylamine (100 mg, 1.33 mmol) was dissolved in DCM (1.5 mL) and DIPEA (344 mg, 2.67 mmol) was added and stirred at room temperature for 0.5 h, p-nitrophenyl chloroformate (320 mg, 1.60 mml) was added, after TLC monitoring showed the disappearance of the starting material, the solvent was removed under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 4-nitrophenyl (2-methoxyethyl)carbamate (200 mg, white solid, yield 62.6%). MS (ESI) M / Z: 241.22 [M+H] +

[0605] Step B: tert-Butyl 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)- 2-oxo-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 h, after liquid chromatography-mass spectrometry monitoring showed the disappearance of the starting material, dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added again and concentrated under reduced pressure until dichloromethane and trifluoroacetic acid were completely removed to give 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4- (piperazin-1-yl)quinolin-2(1H)-one (40 mg, light yellow solid, yield 76.5%). MS (ESI) M / Z: 476.2 [M+H] +

[0606] Step C: 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4- (piperazin-1-yl)quinolin-2(1H)-one (40 mg, 0.11 mmol) was dissolved in THF (1 mL) and KHMDS (0.52 mL) was added and stirred at room temperature for 0.5 h, 4-nitrophenyl (2-methoxyethyl)carbamate (62 mg, 0.261 mml) was added, after 2 h of reaction at 50 °C, LCMS monitoring showed the disappearance of the starting material, the solvent was removed by distillation under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide (45 mg, white solid, yield 92.9%). MS (ESI) M / Z: 577.2 [M+H] +

[0607] 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 10.5 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 7.5 Hz, 2H), 7.13 (t, J = 8.5 Hz, 1H), 6.72 (dd, J = 8.5, 2.5 Hz, 1H), 6.66 (dd, J = 12.0, 2.4 Hz, 1H), 6.54 (d, J = 6.5 Hz, 1H), 6.37 (s, 1H), 4.97 (s, 1H), 3.81 (s, 3H), 3.68 (s, 4H), 3.55 - 3.47 (m, 4H), 3.40 (s, 3H), 3.23 (s, 4H), 2.00 (s, 6H).

[0608] Example 9: 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2- dihydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide

[0609]

[0610] Synthesis route:

[0611]

[0612] Step A: 1-(2-Aminoethoxy)-2-methoxyethane (130 mg, 1.1 mmol) was dissolved in DCM (1.5 mL) and DIPEA (284 mg, 2.2 mml) was added and stirred at room temperature for 0.5 hours, p-nitrophenyl chloroformate (331 mg, 1.65 mml) was added, after 1 h of reaction at room temperature, LCMS monitoring showed the disappearance of the starting material, the solvent was removed under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 4-nitrophenyl (2-(2-methoxyethoxy)ethyl)carbamate (250 mg, white solid, yield 80.0%).

[0613] MS (ESI) M / Z: 285.1 [M+H] +

[0614] Step B: 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-oxo-1,2- dihydroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 hour, after liquid chromatography mass spectrometry monitoring showed the disappearance of the starting material, dichloromethane and trifluoroacetic acid were removed under reduced pressure, and dichloromethane (10 mL) was added again and concentrated under reduced pressure until dichloromethane and trifluoroacetic acid were completely removed to obtain 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1- yl)quinolin-2(1H)-one (40 mg, light yellow solid, yield 76.5%). MS (ESI) M / Z: 476.2 [M+H] +

[0615] Step C: 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4- (piperazin-1-yl)quinolin-2(1H)-one (40 mg, 0.11 mmol) was dissolved in THF (1 mL) and KHMDS (0.52 mL) was added and stirred at room temperature for 0.5 h, 4-nitrophenyl (2-(2-methoxyethoxy)ethyl)carbamate (93.72 mg, 0.33 mml) was added and reacted at 50 °C for 2 h, LCMS monitoring showed that the starting material disappeared, the solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide (42 mg, white solid, yield 61.5%). MS (ESI) M / Z: 621.2 [M+H] +

[0616] 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 10.5 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.13 (t, J = 8.3 Hz, 1H), 6.72 (dd, J = 8.6, 2.4 Hz, 1H), 6.66 (dd, J = 11.9, 2.4 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 6.34 (s, 1H), 5.21 (t, J = 5.3 Hz, 1H), 3.81 (s, 3H), 3.70 - 3.65 (m, 6H), 3.64 - 3.62 (m, 2H), 3.59 - 3.56 (m, 2H), 3.52 - 3.49 (m, 2H), 3.41 (s, 3H), 3.22 (d, J = 4.5 Hz, 4H), 2.00 (s, 6H).

[0617] Example 10: Synthesis of 4-(4-acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-4- methoxyphenyl)-1-(2-isopropylphenyl)quinolin-2(1H)-one

[0618]

[0619] Step A: 2-Bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) was dissolved in anhydrous toluene (110 mL), then 2-isopropylaniline (5.39 g, 39.86 mmol), Pd(OAC)2 (palladium acetate, 0.75 g, 3.34 mmol), BINAP (1,1'-binaphthalene-2,2'-diphosphonic acid, 2.07 g, 3.34 mmol) and cesium carbonate (16.24 g, 49.72 mmol) were added. The reaction was refluxed under nitrogen overnight. After the starting material was consumed by LC-MS, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give N-(3-bromo-4-fluorophenyl)-2-isopropylaniline (9.6 g, yellow oil, yield 93.75%). MS (ESI) M / Z: 308.2 [M+H] + .

[0620] Step B: N-(3-bromo-4-fluorophenyl)-2-isopropylaniline (9.6 g, 31.15 mmol) and methyl 3-chloro-3-oxopropionate (8.5 g, 62.26 mmol) were dissolved in dichloromethane (100 mL), then triethylamine (6.3 g, 62.26 mmol) was slowly added dropwise at room temperature over 1 hour and stirred for 30 minutes. After the starting material was consumed by LC-MS, the reaction solution was diluted with dichloromethane (100 mL) and water (100 mL) was added, the mixture was extracted with dichloromethane (80 mL x 3 times), the organic phase was washed with saturated brine (80 mL x 3 times) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give methyl 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3-oxopropionate (11.2 g, white solid, yield 88.2%). MS (ESI) M / Z: 408.3 [M+H] + .

[0621] Step C: To a solution of 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)- 3-oxopropanoic acid methyl ester (11.2 g, 27.47 mmol) dissolved in methanol (110 mL) was added 56 mL of 2N sodium hydroxide and stirred at room temperature for 1 h. After LCMS monitoring showed the disappearance of starting material, the mixture was diluted with water (100 mL) and then the aqueous phase was adjusted to pH 2 with dilute hydrochloric acid. It was extracted twice with ethyl acetate (2 x 100 mL), the organic layer was washed with brine, dried over Na2S04, filtered and finally concentrated under reduced pressure. This gave 3-((3-bromo-4-fluorophenyl)(2- isopropylphenyl)amino)-3-oxopropanoic acid (g, 9.8 pale yellow solid, yield 90.74%). MS (ESI) M / Z: 394.2 [M+H] + .

[0622] Step D: 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3-oxopropanoic acid (9.8 g, 24.86 mmol) was dissolved in Eatons Reagent (70 mL) and stirred at 70 °C overnight. After LCMS monitoring showed the disappearance of starting material, the reaction solution was slowly added dropwise to saturated sodium bicarbonate solution and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. It was extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. This gave 7-bromo-6-fluoro-l-(2-isopropylphenyl)quinoline-2,4(lH,3H)-dione (7.3 g, white solid, yield 78.07%). MS (ESI) M / Z: 376.2 [M+H] + .

[0623] Step E: 7-bromo-6-fluoro-l-(2-isopropylphenyl)quinoline-2,4(lH,3H)-dione (7.3 g, 19.40 mmol) was dissolved in phosphorus oxychloride (45 mL) and stirred at 80 °C for 6 h. After LCMS monitoring showed the disappearance of starting material, the phosphorus oxychloride was distilled off under reduced pressure, water (40 mL) was slowly added and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. It was extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The solid was dissolved in N,N-dimethylformamide and prepared to give 7-bromo-4-chloro-6-fluoro-l-(2-isopropylphenyl)quinolin-2(lH)-one (2.4 g, pale yellow solid, yield 36.32%). MS (ESI) M / Z: 394.7 [M+H] + .

[0624] Step F: 7-Bromo-4-chloro-6-fluoro-l-(2-isopropylphenyl)quinolin-2(lH)-one (2.4 g, 6.08 mmol) was dissolved in dioxane (20 mL), then tert-butyl piperazine-l-carboxylate (5.65 g, 30.38 mmol) and N,N-diisopropylethylamine (4.72 g, 36.52 mmol) were added and stirred at 110 °C for 2 days. After the disappearance of the starting material was shown by LC-MS, the solvent was removed by distillation under reduced pressure and the resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 5 / 2) to give tert-butyl 4-(7-bromo-6-fluoro-l-(2-isopropylphenyl)-2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylate (2.9 g, white solid, yield 87.88 %). MS (ESI) M / Z: 544.5 [M+H] + .

[0625] Step G: A mixture of tert-butyl 4-(7-bromo-6-fluoro-l-(2-isopropylphenyl)-2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylate (0.500 g, 0.918 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (0.624 g, 3.6717 mmol), potassium acetate (0.54 g, 3.923 mmol) and PdCl2(dppf)1,1'-bis(diphenylphosphino)ferrocene dichloropalladium, 0.134 g, 0.183 mmol) was dissolved in a mixture of 1,4-dioxane and water (8 mL / 2 mL) which was replaced with argon for 15 minutes, replaced with argon again and stirred at 90 °C for 48 h. After the disappearance of the starting material was shown by LC-MS, it was extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 10 / 1) to give tert-butyl 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2-isopropylphenyl)-2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylate (0.340 g, yellowish solid, yield 80.3 %). MS (ESI) M / Z: 589.7 [M+H] + .

[0626] Step H: 4-(6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2-isopropylphenyl)-2-oxo-l,2- dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.340 g, 0.577 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 hour, after liquid mass spectrometry monitoring showed the disappearance of the starting material, the dichloromethane and trifluoroacetic acid were removed under reduced pressure and dichloromethane (10 mL) was added and again concentrated under reduced pressure until the dichloromethane and trifluoroacetic acid were completely removed to obtain 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2- isopropylphenyl)-4-(piperazin-l-yl)quinolin-2(lH)-one (0.281 g, brown solid, yield 99.6%). MS (ESI) M / Z: 489.6 [M+H] + .

[0627] Step I: 6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2-isopropylphenyl)-4-(piperazin-l- yl)quinolin-2(lH)-one (0.281 g, 0.574 mmol) was dissolved in dichloromethane (10 mL) and DIPEA (N,N-diisopropylethylamine) (0.371 g, 2.87 mmol) and acryloyl chloride (0.104 g, 1.15 mmol) were added and stirred at room temperature for 2 hours, after LCMS monitoring showed the disappearance of the starting material, the solvent was removed under reduced pressure and the resulting solid was dissolved in N,N-dimethylformamide (5 mL) to prepare 4-(4-acryloylpiperazin-l-yl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2- isopropylphenyl)quinolin-2(lH)-one (0.0562 g, white solid, yield 17.95%). MS (ESI) M / Z: 543.6 [M+H] +

[0628] 1H NMR (500 MHz, DMSO) δ 7.74 (dd, J = 7.9, 1.3 Hz, 1H), 7.51 (dd, J = 7.7, 1.2 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.30 (dd, J = 16.7, 8.4 Hz, 2H), 7.19 (dd, J = 6.5, 2.3 Hz, 1H), 6.96 (dd, J = 12.2, 2.4 Hz, 1H), 6.87 (ddd, J = 20.9, 10.8, 6.5 Hz, 2H), 6.16 (dd, J = 16.7, 2.3 Hz, 1H), 6.03 (s, 1H), 5.76 - 5.71 (m, 1H), 3.82 (s, 2H), 3.81 (s, 3H), 3.11 (s, 5H), 2.62 - 2.53 (m, 1H), 1.25 (d, J = 11.9 Hz, 1H), 0.84 (d, J = 6.6 Hz, 6H).

[0629] Example 11: Synthesis of 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-7-(2- isopropylphenyl)-2-oxo-l,2-dihydroquinolin-4-yl)-N-(2-methoxyethyl)piperazine- 1-carboxamide

[0630]

[0631] Synthesis route:

[0632]

[0633] Step A: 2-Methoxyethylamine (0.2 g, 2.66 mmol) was dissolved in THF (3 mL) and DIPEA (N,N-diisopropylethylamine) (0.688 g, 5.32 mmol) was added and stirred for 10 min in ice bath, 4-nitrophenyl chloroformate (0.805 g, 3.99 mmol) was added slowly and allowed to warm to room temperature and stirred for 2 h, after the disappearance of starting material was monitored by LC-MS, the solvent was removed under reduced pressure to give 4-nitrophenyl (2-methoxyethyl)carbamate (0.487 g, yellow oil, yield 93.8%) MS (ESI) M / Z: 240.2 [M+H] + .

[0634] Step B: 4-(6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo- 1,2-dihydroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 h, after the disappearance of starting material was monitored by LC-MS, the dichloromethane and trifluoroacetic acid was removed by concentration under reduced pressure and dichloromethane (10 mL) was added again and concentrated under reduced pressure until the dichloromethane and trifluoroacetic acid was completely removed to get 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2- isopropylphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one (0.248 g, brown solid, yield 99.6 %). MS (ESI) M / Z: 489.6 [M+H] + .

[0635] Step C: 6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4- (piperazin-1-yl)quinolin-2(1H)-one (0.248 g, 0.506 mmol) was dissolved in dichloromethane (4 mL) and 4-nitrophenyl (2-methoxyethyl)carbamate (0.243 g, 1.01 mmol) was added, 1M KHMDS (2 ml) was added slowly under ice bath, the ice bath was removed and stirred at 65 °C for 12 h, after the disappearance of starting material was monitored by LC-MS, the solvent was removed by concentration under reduced pressure to get 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-7-(2-isopropylphenyl)-2-oxo-1,2- dihydroquinolin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide (0.0367 g, yellowish solid, yield 12.3 %). MS (ESI) M / Z: 590.7 [M+H] + .

[0636] 1 H NMR (500 MHz, CDC13) δ 7.60 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.18 - 7.15 (m, 2H), 7.09 (d, J = 6.0 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 11.7 Hz, 1H), 6.08 (s, 1H), 4.88 (s, 1H), 3.75 (d, J = 1.8 Hz, 3H), 3.56 (s, 3H), 3.42 (d, J = 9.8 Hz, 5H), 3.31 (d, J = 1.7 Hz, 3H), 3.09 (s, 4H), 2.55 (d, J = 6.5 Hz, 1H), 0.82 (d, J = 6.4 Hz, 6H).

[0637] Example 12: Synthesis of 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2- isopropylphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine- 1-carboxamide

[0638]

[0639] Synthesis route:

[0640]

[0641] Step A (Step A): 2-(2-methoxyethoxy)ethylamine (0.2 g, 1.68 mmol) was dissolved in THF (3 mL) and DIPEA (N,N-diisopropylethylamine) (434 g, 3.36 mmol) was added and stirred for 10 min in ice bath, 4-nitrophenyl chloroformate (0.507 g, 2.51 mmol) was added slowly and allowed to warm to room temperature and stirred for 2 h, after the disappearance of starting material was monitored by LC-MS, the solvent was removed under reduced pressure to obtain 4-nitrophenyl (2-(2-methoxyethoxy)ethyl)carbamate (0.419 g, yellow oil, yield 88.2%) MS (ESI) M / Z: 284.3 [M+H] + .

[0642] Step B (Step B): tert-butyl 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2- isopropylphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred for 1 h at room temperature, after the disappearance of starting material was monitored by LC-MS, the dichloromethane and trifluoroacetic acid was removed under reduced pressure and dichloromethane (10 mL) was added again and concentrated under reduced pressure till the dichloromethane and trifluoroacetic acid was completely removed to obtain 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2- isopropylphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one (0.248 g, brown solid, yield 99.6%). MS (ESI) M / Z: 489.6 [M+H] + .

[0643] Step C: 6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2-isopropylphenyl)-4- (piperazin-l-yl)quinolin-2(lH)-one (0.248 g, 0.506 mmol) was dissolved in dichloromethane (4 mL) and 4-nitrophenyl (2-(2-methoxyethoxy)ethyl)carbamate (0.216 g, 0.76 mmol) was added, 1 M KHMDS (2 ml) was added slowly under ice bath, the ice bath was removed and stirred at 65 °C for 12 h, after the disappearance of starting material was monitored by LC-MS, the solvent was removed under reduced pressure, 4-(6-fluoro-7- 2-fluoro-4-methoxyphenyl)-l-(2-isopropylphenyl)-2-oxo-l,2-dihydroquinolin-4-yl)-N-(2- (2-methoxyethoxy)ethyl)piperazine-l-carboxamide (0.0416 g, yellowish solid, yield 13.1%) was obtained. MS (ESI) M / Z: 634.7 [M+H] + .

[0644] 1 H NMR (500 MHz, CDC13) δ 7.61 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.21 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 7.17 - 7.14 (m, 1H), 7.10 (d, J = 4.1 Hz, 1H), 6.67 (dd, J = 8.5, 2.1 Hz, 1H), 6.65 - 6.59 (m, 1H), 6.08 (s, 1H), 5.10 (s, 1H), 3.75 (s, 3H), 3.56 (dt, J = 9.9, 4.6 Hz, 8H), 3.52 - 3.48 (m, 2H), 3.42 (s, 2H), 3.33 (s, 3H), 3.09 (s, 4H), 2.56 (dt, J = 13.0, 6.5 Hz, 1H), 0.82 (d, J = 6.5 Hz, 6H).

[0645] Example 13: Synthesis of 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2- isopropylphenyl)-4-(4-(3-(2-methoxyethoxy)propanoyl)piperazin-l-yl)quinolin-2(lH)- one

[0646]

[0647] Synthesis route:

[0648]

[0649] Step B: 4-(6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2-isopropylphenyl)- 2-oxo-l,2-dihydroquinolin-4-yl)piperazine-l-carboxylic acid tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and stirred at room temperature for 1 h, after the disappearance of starting material was monitored by LC-MS, the dichloromethane and trifluoroacetic acid was removed by concentration under reduced pressure and dichloromethane (10 mL) was added again and concentrated under reduced pressure until the dichloromethane and trifluoroacetic acid was completely removed to get 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2- isopropylphenyl)-4-(piperazin-l-yl)quinolin-2(lH)-one (0.228 g, brown solid, 91.6% yield). MS (ESI) M / Z: 489.6 [M+H] + .

[0650] Step C: 6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2-isopropylphenyl)-4- (piperazin-l-yl)quinolin-2(lH)-one (0.228 g, 0.466 mmol) was dissolved in dichloromethane (4 mL) and 3-(2-methoxyethoxy)propanoic acid (0.103 g, 0.695 mmol) and triethylamine (0.118 g, 1.15 mmol) was added, followed by BOP reagent (0.226 g, 0.512 mmol) and stirred at room temperature for 12 h, after the disappearance of starting material was monitored by LC-MS, the solvent was removed by concentration under reduced pressure to get 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-l-(2-isopropylphenyl)-4-(4-(3-(2- methoxyethoxy)propanoyl)piperazin-l-yl)quinolin-2(lH)-one (0.0386 g, yellowish solid, 12.2% yield). MS (ESI) M / Z: 619.7 [M+H] + .

[0651] 1H NMR (500 MHz, CDC13) δ 7.60 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 (dd, J = 7.7, 1.3 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.20 (s, 1H), 7.18 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 6.4, 2.3 Hz, 1H), 6.67 (dd, J = 8.5, 2.5 Hz, 1H), 6.62 (dd, J = 11.7, 2.4 Hz, 1H), 6.09 (s, 1H), 3.78 (d, J = 6.6 Hz, 2H), 3.76 - 3.74 (m, 3H), 3.73 - 3.66 (m, 3H), 3.61 - 3.55 (m, 3H), 3.48 (dt, J = 4.3, 3.1 Hz, 3H), 3.32 (d, J = 3.3 Hz, 3H), 3.09 (s, 4H), 2.66 (t, J = 6.6 Hz, 2H), 2.62 - 2.51 (m, 2H), 0.82 (d, J = 6.7 Hz, 6H).

[0652] Example 14: Synthesis of 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-l-(2-isopropyl-4- methyl-3-pyridinyl)-4-[(3S)-3-methyl-4-prop-2-enyl-piperazin-l-yl]quinolin-2-one

[0653]

[0654]

[0655] Step A: 2-isopropyl-4-methyl-pyridin-3-amine (2 g, 13.3 mmol), palladium acetate (147.8 mg, 0.66 mmol), BINAP (808 mg, 1.3 mmol) and cesium carbonate (8.6 g, 26.6 mmol) were added to toluene (30 ml) and stirred at 110 °C under nitrogen for overnight. The reaction was monitored by mass spectrometry. After completion of the reaction, the solvent was evaporated and purified by column chromatography to give N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methylpyridin-3-amine (2.8 g, 8.7 mmol yield: 65%). MS (ESI) M / Z: 323.3 [M+H]+.

[0656] Step B (Step B): N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methylpyridin-3-amine (2.8 g, 8.7 mmol) was dissolved in dichloroethane (30 ml), 3-chloro-3-oxopropionic acid methyl ester (2.4 g, 17.4) was added dropwise to the solution, stirred at 70 degree Celsius overnight, cooled to room temperature, washed with saturated sodium carbonate solution, extracted with ethyl acetate, dried and concentrated to give 3-(3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid methyl ester (4 g crude). MS (ESI) M / Z: 423.4 [M+H]+

[0657] Step C (Step C): 3-(3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid methyl ester (3 g, 7 mmol) was dissolved in methanol (5 ml), 2M sodium hydroxide solution (10 ml) was added dropwise to the solution, stirred for 1 hour, TLC monitored, after the reaction was completed, the PH was adjusted to neutral with 2M hydrochloric acid solution, the solvent was concentrated, purified by flash (acetonitrile / water) to give 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid (2 g, 5 mmol). MS (ESI) M / Z: 409.5 [M+H]+

[0658] Step D (Step D): 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid (2 g, 5 mmol) was dissolved in 5 ml Eaton's reagent, stirred at 80 degree Celsius for 1 hour, cooled to room temperature, added to ice water, adjusted to neutral with 2M sodium hydroxide solution, extracted with ethyl acetate, the solvent was concentrated to give 7-bromo-6-fluoro-1-(2-isopropyl-6-methyl-pyridyl)quinoline-2,4-dione (2 g crude).

[0659] MS (ESI) M / Z: 391.2 [M+H]

[0660] Step E (Step E): 7-bromo-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinoline-2,4-dione (1 g crude) was dissolved in phosphorus oxychloride (8 ml), stirred at 80 degree Celsius for 2 hours, the solvent was concentrated, adjusted to neutral with 2M sodium hydroxide solution, extracted with dichloromethane, the organic phase was concentrated, purified by column chromatography (PE / EA 0~100%) to give 7-bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinolin-2-one (360 mg, 0.88 mmol)

[0661] MS (ESI) M / Z: 408.1 [M+H]

[0662] Step F: 7-Bromo-4-chloro-6-fluoro-l-(2-isopropyl-4-methyl-3-pyridinyl)quinolin- 2-one (360 mg, 0.88 mmol) was dissolved in DMF, N,N-diisopropylethylamine (260 mg, 2 mmol) and (S)-l-N-Boc-2-methylpiperazine (200 mg, 1 mmol) were added and stirred at 60 °C for two hours, the reaction was confirmed complete by mass spectrometry and purified by flash (acetonitrile / water 0-100%) to give tert-butyl (2S)-4-[7-bromo-6-fluoro-l-(2-isopropyl-4-methyl-3-pyridinyl)-2-oxo-4- quinolinyl]-2-methyl-piperazine-l-carboxylate (404 mg, 0.7 mmol 80% yield). MS (ESI) M / Z: 573.1 [M+H]

[0663] Step G: tert-Butyl (2S)-4-[7-bromo-6-fluoro-l-(2-isopropyl-4-methyl-3-pyridinyl)-2- oxo-4-quinolinyl]-2-methyl-piperazine-l-carboxylate (200 mg 0.348 mmol) was dissolved in 1,4 dioxane, to the system was added 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6- phosphaspiro[4.4]nonane (10.16 mg, 0.0348), potassium phosphate (148 mg, 0.7 mmol) 2-fluoro-6-hydroxybenzeneboronic acid (108 mg, 0.7) and tris(dibenzylideneacetone)dipalladium (31 mg, 0.0348 mmol) and stirred at 60 °C overnight after three nitrogen purges, the solvent was evaporated and purified by flash (acetonitrile / water 0-100%) to give tert-butyl (2S)-4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-l-(2-isopropyl-4-methyl-3- pyridinyl)-2-oxo-4-quinolinyl]-2-methyl-piperazine-l-carboxylate (110 mg) 0.18 mmol 52% yield). MS (ESI) M / Z: 605.3 [M+H]

[0664] Step H: tert-butyl (2S)-4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-l-(2-isopropyl-4- methyl-3-pyridyl)-2-oxo-4-quinolinyl]-2-methyl-piperazine-l-carboxylate (55 mg, 0.09 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.5 ml) was added. The reaction was stirred at room temperature for 1 hour, the solvents were evaporated, dichloromethane (2 ml) and N,N-diisopropylethylamine (64 mg, 0.5 mmol) were added and allyl chloride (8 F mg, 0.09 mmol) was added dropwise. The reaction was stirred for half an hour and the reaction was confirmed complete by mass spectrometry. The solvents were evaporated and the residue was purified by flash (acetonitrile / water) to give 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-l-(2-isopropyl-4-methyl-3- pyridyl)-4-[(3S)-3-methyl-4-prop-2-enyl-piperazin-l-yl]quinolin-2-one (22.3 mg, 0.04 mmol, 44% yield). MS (ESI) M / Z: 559.3 [M+H]

[0665] 1 H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.54 (d, J = 4.7 Hz, 1H), 7.77 (dd, J = 10.3, 4.4 Hz, 1H), 7.32 (s, 1H), 7.26 - 7.18 (m, 1H), 6.86 (dd, J = 15.9, 10.6 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.69 (t, J = 8.9 Hz, 1H), 6.41 - 6.30 (m, 1H), 6.25 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.75 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 156.6 Hz, 1H), 4.24 (d, J = 161.2 Hz, 1H), 3.77 - 3.54 (m, 2H), 3.03 (s, 2H), 2.79 (s, 1H), 2.59 (dd, J = 12.8, 6.5 Hz, 1H), 1.92 (t, J = 19.3 Hz, 3H), 1.46 (s, 3H), 1.01 (dd, J = 51.7, 6.3 Hz, 6H).

[0666] Example 15: Synthesis of 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-l-(2-isopropyl-4- methyl-3-pyridyl)-4-[(3R)-3-methyl-4-prop-2-enyl-piperazin-l-yl]quinolin-2-one

[0667]

[0668] Synthetic route as in Example 14

[0669] MS (ESI) M / Z: 559.3 [M+H]

[0670] 1 H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.54 (d, J = 4.7 Hz, 1H), 7.77 (dd, J = 10.3, 4.4 Hz, 1H), 7.32 (s, 1H), 7.22 (dd, J = 15.4, 8.1 Hz, 1H), 6.86 (dd, J = 16.0, 10.6 Hz, 1H), 6.73 (t, J = 7.8 Hz, 1H), 6.69 (t, J = 8.9 Hz, 1H), 6.40 - 6.30 (m, 1H), 6.25 (s, 1H), 6.19 (t, J = 13.6 Hz, 1H), 5.79 - 5.72 (m, 1H), 4.67 (d, J = 155.9 Hz, 1H), 4.24 (d, J = 160.8 Hz, 1H), 3.69 (d, J = 66.1 Hz, 2H), 3.50 - 3.41 (m, 1H), 3.05 (s, 1H), 2.79 (s, 1H), 2.66 - 2.54 (m, 1H), 1.90 (d, J = 19.8 Hz, 3H), 1.46 (s, 3H), 1.09 - 0.94 (m, 6H).

[0671] Biological activity

[0672] Test method (1)

[0673] Experimental materials:

[0674] KRAS G12C (SignalChem, Cat. No. R06-32DH-BULK)

[0675] SOS1 exchange domain (564-1049) protein (Cytoskeleton, Inc., Cat. No. GE02-XL)

[0676] Transcreener GDP FI Assay (BellBrook, Cat. No. 3014-1K)

[0677] 384-well plate (Perkin Elmer, Cat. No. 6007279)

[0678] BAY-293 (MCE, Cat. No. HY-114398)

[0679] AMG-510 (MCE, Cat. HY-114277)

[0680] Experimental procedure:

[0681] 1. Compound treatment

[0682] Prepare 400x final concentration of compound, e.g. for a final concentration of 25 μΜ, prepare 10 mM. Dilute the compound in a gradient using an automated microplate pipettor to the number of concentration points set.

[0683] 2. Transfer compound to 384 well plate reaction plate

[0684] Transfer 75 nL of the diluted compound from the Echo 384 well plate to the 384 well reaction plate using an ultrasonic nanoliter liquid handling system. Transfer 75 nL of 100% DMSO for the negative and positive controls.

[0685] 3. Prepare 1x reaction buffer

[0686] 1x reaction buffer contains 50 mM Tris (pH 7.5), 50 mM NaCl, 1 mM EDTA, 0.1% BSA, 14 mM MgCl2, 0.01% Tween-20, 1 mM DTT.

[0687] 4. Prepare 3x KRAS G12C enzyme solution, 6x SOS1 enzyme solution, 6x GTP (Bell Brook, Cat. No. 3014-1K) solution, 3x detection solution

[0688] Prepare 3x KRAS G12C enzyme solution, 6x SOS1 enzyme solution, 6x GTP solution, 3x detection solution (Antibody-IRDye and GDP-Tracer) using 1x reaction buffer.

[0689] 5. Transfer 3x KRAS G12C enzyme solution

[0690] Transfer 10 μL of 3x KRAS G12C enzyme solution to the reaction plate. For the negative control wells, replace the enzyme solution with 10 μL of 1x reaction buffer. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes.

[0691] 6. Transfer 6x SOS1 enzyme solution

[0692] Transfer 5 μL of 6x SOS1 enzyme solution to the reaction plate.

[0693] 7. Transfer 6x GTP solution

[0694] Transfer 5 μL of 6x GTP solution to the reaction plate.

[0695] 8. Transfer 3x detection solution

[0696] Transfer 10 μL 3-fold detection solution to the reaction plate. Centrifuge at 1000 rpm for 1 minute.

[0697] 9. Readings

[0698] Read the fluorescence signal (Ex 580 / Em 620) values continuously for 2 hours (every 5 minutes) using a SpectraMax Paradigm plate reader.

[0699] 10. Inhibition rate calculation and IC 50 Fitting

[0700] Copy the values from the plate reader and calculate the slope value, where the maximum value is the reading of the positive control and the minimum value is the reading of the negative control. Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) x 100%.

[0701] Import the data into MS Excel and fit the IC 50 values using XLFit excel add-in version 5.4.0.8.

[0702] Fitting formula: Y = Bottom + (Top-Bottom) / (1+(IC 50 / X)^HillSlope).

[0703] The inhibition rate of the compound of the present application on KRAS G12C at 1 μM and 10 μM, the IC 50 of the compound of the present application for inhibiting KRAS G12C are shown in Table 1.

[0704] Test method (2)

[0705] Detection method: CTG method

[0706] Experimental method:

[0707] 1. Resuspend the cells in the logarithmic growth phase in the growth medium and dilute to the target density. Seed the above cell suspension into a 96-well plate at 100 μL per well, and incubate overnight in a 37°C, 5% CO2 incubator.

[0708] 2. Dissolve the test compound in DMSO to prepare a stock solution with a concentration of 10 mM. First dilute the stock solution to 2 mM with DMSO, 10 concentrations, 3-fold gradient dilution. Then dilute to 30 μM with the growth medium. Add to the 96-well plate seeded with cells at 50 μL / well.

[0709] 3. Incubate the cells added with the test compound in a 37°C, 5% CO2 incubator for 72 hours. Equilibrate the 96-well plate at room temperature, and add 40 μL Reagent (Promega G7573), mix for 2 minutes, incubate at room temperature for 60 minutes, read luminescence value with EnVision R Multilabel Reader, calculate IC50 of compound with GraphPad Prism 5.0 software 50 .

[0710] Test method (3)

[0711] Western Blot protocol

[0712] Cell plating:

[0713] 1. Resuspend cells in log phase in growth medium and dilute to target density. Seed 2 ml per well of the above cell suspension into 6-well plates and incubate at 37°C, 5% CO2 incubator overnight.

[0714] 2. Dissolve the test compound in DMSO and prepare a stock solution at a concentration of 10 mM. First dilute the stock solution to 3 mM, 2 mM, 1 mM with DMSO, respectively, and then dilute to 150 μM, 100 μM, 50 μM with growth medium, respectively. Discard the medium in the 6-well plates and add 200 μl of the diluted compound to make the volume of the 6-well plates 2 ml. Incubate at 37°C, 5% CO2 incubator for 8 hours, 24 hours, 48 hours, respectively.

[0715] Sample preparation (8 hours, 24 hours, 48 hours)

[0716] 1. Equilibrate the 6-well plates to room temperature.

[0717] 2. Resuspend the cells with 150 μL of RIPA lysis buffer containing protease / phosphatase inhibitors and incubate the samples on ice for 30 minutes to complete cell lysis.

[0718] 3. Centrifuge the samples at 13000 rpm, 4°C for 10 minutes to precipitate. Quantify with BCA and prepare the protein samples with 4X loading buffer, boiling at 95°C water bath for 15 minutes.

[0719] WB experimental procedure

[0720] 1. Add 15 μL of cell lysate to the SDS-PAGE gel and run at 200 v for 40 minutes until the blue band is detached from the gel.

[0721] 2. Transfer the gel to the PVDF membrane using electrotransfer (2.5 A, 3 minutes).

[0722] 3. Incubate the PVDF membrane with 5% BSA buffer at room temperature for 1 hour.

[0723] 4. Primary antibody incubation: Dilute antibodies KRAS (1 : 1000) and a-tubulin (1 : 1000), 4°C overnight.

[0724] 5. Secondary antibody incubation: Dilute antibodies 1 : 3000, incubate 1 hour at room temperature.

[0725] 6. Develop using Western ECL developer.

[0726] Results of protein degradation are shown in Table 1.

[0727] Table 1

[0728]

[0729]

[0730]

[0731]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is 2. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is 3. A pharmaceutical composition comprising the compound as described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

4. The pharmaceutical composition according to claim 3, characterized in that, The compound or a pharmaceutically acceptable salt thereof is a therapeutically effective amount.

5. The use of a compound as described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 3 or 4, in the preparation of a KRAS modulator.

6. The application as described in claim 5, characterized in that, The KRAS modulator mentioned is a KRAS inhibitor or a KRAS agonist.

7. The application as described in claim 5, characterized in that, The KRAS regulator mentioned is the KRAS G12C regulator.

8. The use of a compound as described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 3 or 4, in the preparation of a medicament for the prevention and / or treatment of KRAS-related diseases.

9. The application as described in claim 8, characterized in that, The KRAS-related disease mentioned is cancer.

10. The application as described in claim 9, characterized in that, The KRAS-related diseases are lung cancer, pancreatic cancer, pancreatic ductal carcinoma, colorectal cancer, colon cancer, rectal cancer, appendiceal cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, or breast cancer.

11. The application as described in claim 8, characterized in that, The KRAS mentioned is KRAS G12C.

12. The use of a compound as described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 3 or 4, in the preparation of a medicament for the prevention and / or treatment of cancer.

13. The application as described in claim 12, characterized in that, The cancers mentioned are lung cancer, pancreatic cancer, pancreatic ductal carcinoma, colorectal cancer, colon cancer, rectal cancer, appendiceal cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, or breast cancer.

Images